Towards a stable noeuromycin analog with a d-manno configuration: Synthesis and glycosidase inhibition of d-manno-like tri- and tetrahydroxylated azepanes

Article abstract of DOI:10.1016/j.bmc.2010.09.053

Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable d-gluco-like analogs have been reported, no data are available for d-manno-like structures. A series of tri- and tetrahydroxylated seven-memb

Full text of DOI:10.1016/j.bmc.2010.09.053

Bioorganic & Medicinal Chemistry 20 (2012) 641–649
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Towards a stable noeuromycin analog with a D-manno configuration:
Synthesis and glycosidase inhibition of D-manno-like tri- and tetrahydroxylated
azepanes
Julia Deschamp a, Martine Mondon d, Shinpei Nakagawa b, Atsushi Kato b, Dominic S. Alonzi c,
a,d,
Terry D. Butters c, Yongmin Zhang a, Matthieu Sollogoub a, , Yves Blériot
⇑
⇑
a UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, C-181, 4 place Jussieu F-75005 Paris, France
b Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
c Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QY, UK
d Université de Poitiers, UMR-CNRS 6514, Laboratoire de Synthèse et Réactivité des Substances Naturelles, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2010
Revised 14 September 2010
Accepted 22 September 2010
Available online 1 October 2010
Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function.
While stable
A series of tri- and tetrahydroxylated seven-membered iminosugars displaying either a
gulo-like configuration, were synthesized from methyl -mannopyranoside using a reductive amina-
D-gluco-like analogs have been reported, no data are available for
D
-manno-like structures.
D-manno-or a L-
a-D
tion-mediated ring expansion as the key step. Screening towards a range of commercial glycosidases
demonstrated their potency as competitive glycosidase inhibitors while cellular assay showed selective
albeit weak glycoprotein processing mannosidase inactivation.
Keywords:
Azepane
Glycosidase
Iminosugar
Inhibition
Sugar mimic
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
414 and noeuromycin 515 have been reported and proved to be
potent glycosyl hydrolase inhibitors. Their conformational flexibil-
The quest for strong and selective glycosidase inhibitors is the
subject of intensive research from many synthetic and biochemical
groups as glycosidases are involved in an increasing number of
pathologies1 which require innovative structures able to selec-
tively and strongly inhibit these therapeutically relevant enzymes.
The most studied and promising structures to date are iminosug-
ars,2 sugar analogs in which a nitrogen atom is replacing the endo-
cyclic oxygen. They have been devised to act as stable mimics of
the glycosidase transient oxacarbenium-like transition state. These
molecules can modulate cellular functions and promising results
have been obtained in the field of diabetes,3 HIV,4 viral infections,5
cancer6 and lysosomal storage diseases7 leading in some cases to
therapeutics.8
ity has been also exploited to have insight into the glycosidase-
mediated substrate ring distorsion performed by O-GlcNAcase,16
a cytoplasmic b-N-acetylglucosaminidase.17 Interestingly, a N-
butylated azepane 618 proved to be a potent inactivator of cera-
mide glucosyl transferase, an enzyme targeted in Gaucher dis-
ease,19 the most prominent lysosomal storage disorder. More
recently it has been shown that compound 6 and congeners, albeit
Our group9 and others10 have focused on the design of unusual
seven-membered iminosugars also named polyhydroxylated aze-
panes (Fig. 1). Seven-membered analogs of lead six-membered
iminosugars including 1-deoxynojirimycin 1,11 1-deoxymannojiri-
mycin 2,12 2-acetamido-1,2-dideoxynojirimycin 3,13 nojirimycin
⇑
Corresponding authors.
E-mail addresses: matthieu.sollogoub@upmc.fr (M. Sollogoub), yves.bleriot@
univ-poitiers.fr (Y. Blériot).
Figure 1. Structure of iminosugars 1–6.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.09.053

642
J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
Figure 2. Structure of target iminosugars 7–10.
displaying a
D-gluco- or
L-ido-like configuration, were selective and
plen deacetylation yielded the azidolactol 1223 in 75% yield as a
potent cytosolic mannosidase inhibitors, thus allowing to probe
mixture of anomers. Ring expansion was examined next. We have
glycoprotein degradation pathways in cells.20
previously reported the ring isomerisation of 6-azido-6-deoxy-
glucopyranose to generate -gluco-configured noeuromycin homo-
logs. In this latter work, hydrogenation of the -gluco-configured
D-
The configurational mismatch observed for compound
prompted us to explore the synthesis and determine the glycosidase
inhibition profile of a series of -manno-like tri- and C-6 epimeric
tetrahydroxylated azepanes 7–10 (Fig. 2). Furthermore compounds
7 and 9 can be seen as -manno configured noeuromycin ring homo-
6
D
D
D
azidolactol in the presence of triethylamine to avoid hydrogenoly-
sis of the benzyl ethers failed to furnish the expected b-hydrox-
yazepane in satisfactory and reproductible yield while the
alternative Staudinger-azaWittig methodology was more success-
ful. Unfortunately, when applying the latter conditions to the
D
logs. Noeuromycin has been designed to mimic the carbocationic
form of the glycosidase transition state and is a very potent and
promising glycosidase inhibitor. Unfortunately its hemiaminal
makes it unstable at neutral pH which has precluded its therapeutic
development so far.15 It is stable for a month as its hydrochloride
D-manno-configured azidolactol 12, the corresponding hydrox-
yazepane 13 was obtained in low yield. Surprisingly, hydrogena-
tion-mediated ring expansion applied to the 6-azido-6-deoxy-
mannopyranose 12 yielded the desired hydroxyazepane 13 in good
yield (85%) emphasizing the opposite behavior of these azidolac-
tols during ring expansion which can be related to the distinct ste-
reochemistry of the hydroxyl groups present on the azepane ring
eventually yielding to more or less stable hemiaminal bicyclic
intermediates as previously observed.24 Chemoselective protection
of the amine in 13 as its benzyl carbamate yielded the azepane 14
(91%) ready for homologation of the free hydroxyl group
(Scheme 1).
salt, existing as a 1:2 mixture of
species, but undergoes Amadori rearrangement at neutral pH. While
chemically stable analogs of -gluco-configured noeuromycin ana-
logs have reported through 2-hydroxyl group homologation,21 no
derivative with a strict -manno-like configuration has been de-
D-gluco and D-manno configured
D
D
scribed to the best of our knowledge. Regarding the crucial role of
mannosidases in biochemical pathways and the potency of 1-N-imi-
nosugars, there is a need for noeuromycin analogs displaying a
D-manno configuration.
Oxidation with PCC furnished the corresponding ketone 15
(87%). Unlike the D-gluco isomer, olefination of 15 under standard
Wittig conditions proved to be problematic and yielded the desired
exoalkene 16 only in low yield (Scheme 2).
2. Synthesis
Our strategy towards target azepanes 7–10 is based on the ring
Optimization of the olefination step was thus necessary (Table
1). While temperature and amount of ylide introduced had no
noticeable effect on the yield (entries 1–6), ylide concentration
proved to influence the reaction outcome (entries 8 and 9). Most
importantly, reverse addition greatly improved the yield (entries
6 and 7) and the best conditions (entry 9) furnished the expected
exoalkene 16 in 50% yield. Use of other olefination reagents such
expansion of an azidolactol derived from
Staudinger/aza Wittig reaction22 and requires the 6-azido-6-
deoxy- -mannopyranose which was synthesized as follows.
Commercially available methyl -mannopyranoside was regio-
selectively tosylated at C-6, displaced with sodium azide and perb-
enzylated to furnish the azide 11 in 65% yield over three steps.
Acetolysis of the anomeric methoxy group in 11 followed by Zem-
D-mannose via a tandem
D
a-D
Scheme 1. Synthesis of hydroxyazepane 14.
Scheme 2. Synthesis of exoalkene 16.

J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
643
Table 1
Optimization of the olefination conditions
Entry
Order of addition
Temperature
Equiv of PPh3CH2Bra
Yield (%)
1
2
3
4
5
6
7
8
9
Normal
Normal
Normal
Normal
Normal
Normal
Reverse
Reverse
Reverse
Reverse
—
ꢁ78 °C
10
10
10
10
2
30
10
15b
15
15
Traces
Traces
Traces
Traces
Traces
Traces
20%
30%
50%
15%
10%
0 °C
ꢁ20 °C
ꢁ10 °C then rt
ꢁ10 °C then rt
ꢁ10 °C then rt
ꢁ10 °C then rt
ꢁ10 °C then rt
ꢁ10 °C then rt
ꢁ10 °C then 60 °C
10
11
12
Tebbe reagent, PhCH3, 0 °C to rt
Petasis reagent, PhCH3, 80 °C
—
<10%
a
0.007 M solution in THF.
0.02 M solution in THF.
b
as Tebbe reagent25 or Petasis reagent26 (entries 11 and 12) was
unsuccessful.
7–10 display competitive inhibition, and, unlike the
D
-gluco- and
L-ido-like azepanes which showed a marked selectivity towards glu-
Since the 3,4,5-trihydroxy-6-methyl derivatives in the D-gluco
cosidases, the -manno and -gulo derivatives inhibit a broad range
D
L
series were found to be as potent glycosidase inactivators as the
3,4,5-trihydroxy-6-hydroxymethyl derivatives,18 functionalization
of the C@C bond by hydroboration and hydrogenation was per-
formed. Hydroboration of 16 with 9-BBN was found sluggish and
replaced by BH3ꢀTHF which, after oxidation, furnished the separa-
ble hydroxymethyl derivatives 17a and 17b as the main products
(50%) along with tertiary alcohols. Final hydrogenolysis quantita-
tively afforded the target azepanes 7 and 8 (Scheme 3).
In parallel, treatment of exoalkene 16 with Wilkinson’s catalyst
yielded the two separable 6-methyl azepanes 18a and 18b (70%
yield, 2:1 ratio) which were quantitatively deprotected to afford
the trihydroxylated azepanes 9 and 10 (Scheme 4).
of glycosidases. Unfortunately, no trend toward a specific mannos-
idase inactivation was observed. The presence of a methyl or
hydroxymethyl group at position 6 with a R configuration appears
to be detrimental as azepanes 7 and 9 were less potent than aze-
panes 8 and 10 towards the range of glycosidases assayed except
a-L-fucosidase. The trihydroxylated azepane 10 is more potent than
the tetrahydroxylated azepane 8 indicating that the methyl group at
C-6 is better accommodated by the glycosidase active site. Azepane
10 is the most potent inhibitor in this series and exhibits IC50 in the
low micromolar range for three glycosidases (rice
a-glucosidase,
almond b-glucosidase and coffee beans -galactosidase). This poor
a
selectivity can be related to the pseudosymmetry of this azepane
as broad range glycosidase inhibition has been previously observed
in the case of C-2 symmetrical tetrahydroxylated azepanes. 10d
2.1. Inhibition of glycosidases from various sources
Polyhydroxylated azepanes 7–10 were assayed on a panel of
commercially available glycosidases. The following glycosidases
were not inhibited at 1 mM: b-mannosidase from snail, a-L-rham-
2.2. Inhibition of glycosidases involved in glycoprotein
degradation pathways
nosidase from Penicillium decumbens, trehalase from porcine
kidney, amyloglucosidase from Aspergillus niger. The four azepanes
Multiple isoforms of mammalian
the pathways of N-linked glycoprotein synthesis and catabolism.
a-mannosidases are active in
Scheme 3. Synthesis of target azepanes 7 and 8.
Scheme 4. Synthesis of target azepanes 9 and 10.

644
J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
They differ in specificity, function and location within the cell and
can be selectively inhibited by iminosugar monosaccharide mim-
ics. In a previous study, a series of structurally related novel se-
ven-membered iminocyclitols were found to be potent and
selective cytosolic a-mannosidase inhibitors while displaying con-
figurations that did not match the stereochemical preference of the
3. Conclusion
A series of new tri- and tetrahydroxylated seven-membered
iminosugars displaying either a
ration have been synthesized with the aim to generate stable
-manno configured noeuromycin analogs. They have been assayed
D-manno- or a L-gulo-like configu-
D
glycosidase. In this work, we aimed at detecting inhibition of mam-
towards a range of commercial glycosidases and demonstrated
competitive, potent but non selective glycosidase inhibition. No
malian mannosidase by azepanes 7–10 displaying either a
no or -gulo like configuration through analysis of the free
oligosaccharides (FOS)27 as markers of endoplasmic reticulum
D-man-
L
significant jack bean
a-mannosidase inhibitory activity was ob-
served. When shifting to cellular assay, weak glycoprotein process-
(ER), Golgi, lysosomal and cytosolic
(Table 2). The four azepanes are weak
a
-mannosidase activities
ing mannosidase inactivation was observed with azepanes 7 and 9
a-mannosidase inhibitors
displaying a
D-manno-like configuration, these two compounds
in cells and effects are seen only at 1 mM (Figure 3). Interestingly
and unlike assays above, only the azepanes 7 and 9 displaying a
acting in a similar manner as swainsonine. The low degree of inhi-
bition recorded might be due to the absence of N-alkyl chain
known to facilitate cell penetration. Work is in progress to put this
hypothesis on firmer ground.
D
-manno-like configuration significantly inhibit
a
-mannosidase
-gulo
and have similar potency at 1 mM. Azepanes 8 and 10 with a
L
like configuration do not inhibit these enzymes at the concentra-
tions tested. We have used a lysosomal inhibitor, swainsonine, as
control and azepanes 7 and 9 appear to act in a similar manner,
4. Experimental section
4.1. General
increasing the amount of core Man3GlcNAc2(Man
a1,3
(Man 1,6)Manß1,4GlcNAcß1,4GlcNAc) as a product of lysosomal
a
mannosidase inhibition. The generation of additional species in
treated cells including Man5–8GlcNAc2FOS confirm lysosomal inhi-
bition, but the significant increase in Man5GlcNAc1also supports
inhibition of the cytosolic mannosidase (Figs. 3 and 4), similar to
the effects seen using the seven-membered iminocyclitols pub-
lished previously.20
NMR spectra were recorded on Bruker spectrometers (400 MHz
for 1H, 100 MHz for 13C). Chemical shifts are reported in d ppm
from tetramethylsilane with the solvent resonance as the internal
standard for 1H NMR and chloroform-d (d 77.0 ppm) for 13C NMR.
Coupling constants (J) are given in hertz. Following abbreviations
classify the multiplicity: s = singlet, d = doublet, t = triplet,
Table 2
Inhibition profile of polyhydroxylated azepanes 7–10
Enzyme
IC50 lm
H.HCl
N
H.HCl
H.HCl
N
H.HCl
N
N
HO
HO
OH
OH
OH
OH
HO
HO
HO
HO
OH
OH
OH
OH
10
7
9
8
a
-Glucosidase
Rice
Yeast
NI (0%)
NI (18.7%)
NI (14.7%)
71
226
NI (0%)
12
NI (37.8%)
b-Glucosidase
Almond
Bovine liver
NI (41.4%)
447
157
432
NI (29.4%)
NI (49.2%)
14
244
a
-Galactosidase
Coffee beans
NI (16.8%)
442
65
NI (37.6%)
876
14
b-Galactosidase
Bovine liver
420
198
a
-Mannosidase
Jack beans
NI (23.0%)
NI (0%)
812
335
101
b-Mannosidase
Snail
NI (0%)
NI (1.5%)
NI (25.0%)
594
NI (4.3%)
NI (6.8%)
181
NI (0.4%)
NI (20.6%)
64
a
-
L
-Rhamnosidase
P. decumbens
NI (0.9%)
NI (15.8%)
NI (0%)
a-L-Fucosidase
Bovine kidney
b-Glucuronidase
Bovine liver
NI (0%)
NI (22.2%)
NI (0%)
139
Trehalase
Porcine kidney
NI (16.6%)
NI (14.2%)
NI (17.2%)
NI (0.3%)
NI (39.9%)
NI (6.9%)
Amyloglucosidase
Aspergillus niger
a
NI: no inhibition (less than 50% inhibition at 1000 lM).
b
(ꢀ ꢀ ꢀ): inhibition % at 1000
lM.

J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
645
Figure 3. HPLC analysis of 2-AA fluorescently labeled FOS after treatment with azepanes 7–10. The top two panels shows levels of mannosylated free glycans in untreated
MDBK cells and swainsonine (1 mM for 24 h) treated cells, respectively.
Figure 4. An overlay comparison ofthe HPLC analysis of 2-AA fluorescently labeled FOS from MDBK cells, untreated or following treatment with swainsonine and azepane 9,
shown in Figure 3.
q = quartet, m = mutiplet, br = broad signal. All assignments were
confirmed by the aid of two-dimensional experiments (1H, 1H
and 1H, 13C). The high-resolution mass spectra (HRMS) were ob-
tained by the electrospray ionization method (Bruker Daltonics
4.1.1. 1-Methyl-6-azido-2,3,4-tri-O-benzyl-6-deoxy-a-D-
mannopyranoside (11)
This compound 11 was synthesized according to the reported
procedure.22 (65% yield); 1H NMR (400 MHz, CDCl3): d 7.42–7.28
(m, 15H, CH-Ar); 4.99 (d, 2J = 11.0 Hz, 1H, CH2-Bn); 4.80 (d,
2J = 12.5 Hz, 1H, CH2-Bn); 4.74 (d, 2J = 12.4 Hz, 1H, CH2-Bn); 4.73
(m, 1H, H1); 4.64 (m, 2H, CH2-Bn); 4.62 (d, 2J = 11.1 Hz, 1H, CH2-
Bn); 3.91–3.39 (m, 2H, H3 and H4); 3.82 (m, 1H, H2); 3.79–3.77
(m, 1H, H5); 3.49–3.42 (m, 2H, H6); 3.37 (s, 3H, OCH3). 13C NMR
microTOF). ½a 2D0
ꢂ
values were measured on a Perkin–Elmer 241
MC Polarimeter (concentration c are given in g/100 mL). Tetrahy-
drofuran, toluene and dichloromethane were distilled respectively
under argon over sodium/benzophenone, sodium and calcium
hydride.

646
J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
(100 MHz, CDCl3): d 138.3, 138.2, 138.1 (Cquat-Ar); 129.7, 129.0,
128.5, 128.4, 127.9, 127.8, 127.7, 127.6 (CH-Ar); 98.9 (C1); 75.2
and 80.0 (C3 and C4); 51.5 (C6); 75.0 (CH2-Bn); 74.3 (C2); 72.7
(CH2-Bn); 72.0 (CH2-Bn); 71.5 (C5); 54.9 (OCH3).
3H, H3, H4, and H6); 3.91 (dd, 3J = 6.6 Hz and 4.2 Hz, 1H, H5); 3.14
(dd, 2J = 13.9 Hz and3J = 6.3 Hz, 1H, Ha of CH2); 3.00 (dd,
2J = 13.9 Hz and3J = 6.3 Hz, 1H, Hb of CH2); 3.00 (dd, 2J = 14.2 Hz
and3J = 7.3 Hz, 1H, Ha of CH2); 2.90 (dd, 2J = 14.2 Hz and
3J = 7.3 Hz, 1H, Hb of CH2); 2.46 (s, 2H, OH + NH).13C NMR
(100 MHz, CDCl3): d 138.55, 138.5, 138.0 (Cquat-Ar); 128.5, 128.3,
128.0, 127.9, 127.7, 127.6, 127.5 (CH-Ar); 80.4, 79.8, 78.0 (C3, C5,
andC6); 73.7 (CH2-Bn); 73.3 (CH2-Bn); 72.0 (CH2-Bn); 69.9 (C4);
4.1.2. 6-Azido-2,3,4-tri-O-benzyl-6-deoxy-D-mannopyranoside
(12)
To a cooled solution of methyl-6-azido-2,3,4-tri-O-benzyl-6-
deoxy- -mannopyranoside 11 (2 g, 4.1 mmol) in dichlorometh-
ane (40 mL) at ꢁ10 °C were added dropwise acetic anhydride
(3.0 mL, 20.5 mmol, 5 equiv) and sulfuric acid (240 L, 4.1 mmol,
a-
D
48.7, 48.5 (C2 and C7).½a D20
= ꢁ26.0 (c 0.75 CHCl3). HRMS (+ESI):
ꢂ
calcd for C27H32O4N: 434.2326; found: 434.2328.
l
1 equiv). The reaction mixture was stirred at ꢁ10 °C for 5 min
(the completion of the reaction was monitored by TLC). The reac-
tion mixture was diluted with ethyl acetate, and then was
quenched with ice. The aqueous layer was extracted twice with
ethyl acetate. The combined organic layers were successively
washed with water, sodium bicarbonate (twice), water and brine,
dried over magnesium sulfate, filtered and evaporated under re-
duced pressure. The residue was purified by flash chromatography
(cyclohexane/ethyl acetate: 5:1) to afford the acetate anomer as a
colorless oil (1.8 g, 86% yield); 1H NMR (400 MHz, CDCl3) d
7.33–7.18 (m, 15H, CH-Ar); 6.10 (d, 3J = 2.0 Hz, 1H, H1); 4.89 (d,
2J = 10.9 Hz, 1H, CH2-Bn); 4.70 (d, 2J = 12.6 Hz, 1H, CH2-Bn); 4.64
(d, 2J = 12.6 Hz, 1H, CH2-Bn); 4.53 (d, 2J = 10.9 Hz, 1H, CH2-Bn);
4.51 (s, 2H, CH2-Bn); 3.93 (dd ? t, 3J = 9.6 Hz and 9.5 Hz, 1H, H4);
3.75 (dd, 3J = 9.4 Hz and 3.1 Hz, 1H, H3); 3.72 (m, 1H, H5); 3.66
(dd, 3J = 3.0 Hz and 2.2 Hz, 1H, H2); 3.45 (dd, 2J = 9.9 Hz
and3J = 1.7 Hz, 1H, H6b); 3.30 (dd, 2J = 9.9 Hz and 3J = 4.1 Hz, 1H,
4.1.4. (3R,4R,5R,6R)-N-Benzyloxycarbonyl-3-hydroxy-4,5,6-
tribenzyloxyazepane (14)
To a cooled biphasic solution of (3R,4R,5R,6R)-3-hydroxy-4,5,
6-tribenzyloxyazepane 13 (443 mg, 1.02 mmol) in ethyl acetate/
water (15 mL/15 mL) at 0 °C were dropwise added potassium
bicarbonate (185 mg, 1.83 mmol, 1.8 equiv) and benzyl chlorofor-
mate (330 lL, 2.76 mmol, 2.7 equiv). The completion of the reac-
tion was monitored by TLC (CH2Cl2/CH3OH; 20:1). After 3 h, the
reaction mixture was separated and the aqueous layer was ex-
tracted with ethyl acetate. The combined organic layers were suc-
cessively washed with water, a HCl solution (1 M), water and brine,
dried over magnesium sulfate, filtered and evaporated over re-
duced pressure. The crude product was purified by flash chroma-
tography (cyclohexane/ethyl acetate; 4:1 then 2:1) to afford
azepane 14 as a colorless oil (558 mg, 97% yield); 1H NMR
(400 MHz, CDCl3): d (presence of two rotamers) 7.35–7.18 (m,
40H, CH-Ar); 5.01 (d, 2J = 12.4 Hz, 1H, Ha of CH2-Bn); 4.96 (d,
2J = 12.4 Hz, 1H, Hb of CH2-Bn); 4.90 (d, 2J = 12.4 Hz, 1H, H0a of
CH2-Bn); 4.85 (d, 2J = 12.4 Hz, 1H, Hb0 of CH2-Bn); 4.73–4.30 (m,
H
6a); 1.95 (s, 3H, Ac). 13C NMR (100 M Hz, CDCl3) d168.8 (C@O es-
ter); 138.1, 138.0, 137.1 (Cquat-Ar); 128.5, 128.4, 128.1, 128.0,
127.95, 127.9, 127.8, 127.7 (CH-Ar); 91.5 (C1); 79.0 (C3); 75.4
(CH2-Bn); 74.6 (C4); 73.6 (C5); 73.3 (C2); 72.5 (CH2-Bn); 72.0
(CH2-Bn); 51.1 (C6); 20.9 (CH3).
12H, 3 ꢃ CH2-Bn + 3 ꢃ CH0 -Bn); 4.14 (s, 1H, OH); 4.14–3.73 (m,
2
8H, H3, H4, H5, H6, and H0 , H0 , H0 , H0 ); 3.70–3.47 (m, 8H, H2,
3
4
5
6
H7 + H02, H70 ). 13C NMR (100 MHz, CDCl3): d (presence of two rota-
mers) 157.0, 156.0 (2 ꢃ C@O); 138.5, 138.4, 138.3, 138.2, 138.0,
137.7, 136.7, 136.6 (Cquat-Ar); 128.5, 128.45, 128.4, 128.3, 128.1,
128.0, 127.9, 127.8, 127.7, 127.65, 127.6, 127.5 (CH-Ar); 79.2,
78.6 (CH and CH0); 77.8, 77.7 (CH and CH0); 75.5, 75.4 (CH and
CH0); 73.9, 73.7 (CH2-Bn and C0H2-Bn); 71.8, 71.7 (CH2-Bn and
C0H2-Bn); 70.3 (CH2-Bn); 69.2 (CH); 67.3, 067.1 (CH2-Bn and
To a solution of 1-acetyl-6-azido-2,3,4-tri-O-benzyl-6-deoxy-D-
mannopyranoside (1.8 g, 3.5 mmol) in methanol (40 mL) was
added sodium (160 mg, 7.0 mmol, 2 equiv) by portions. The reac-
tion mixture was stirred at room temperature for 1 h. The comple-
tion of the reaction was monitored by TLC (cyclohexane/acetone;
30:1). The reaction mixture was neutralized with amberlyst 15 re-
sin, filtered and evaporated under reduced pressure. The crude
product was purified by flash chromatography (cyclohexane/ethyl
acetate: 5:1 then 4:1) to afford azidolactol 12 as a pale yellow oil
(1.45 g, 87% yield); 1H NMR (400 M Hz, CDCl3): d 7.42–7.28 (m,
15H, CH-Ar); 5.26–5.24 (m, 1H, H1); 5.00–4.60 (m, 6H, 3 ꢃ
CH2-Bn); 4.00–3.88 (m, 3H, H3, H4 and H5); 3.84 (m, 1H, H2);
3.56–3.52 (m, 1H, H6b); 3.47–3.37 (m, 1H, H6a); 2.95 (br, OH). 13C
NMR (100 M Hz, CDCl3): d 138.2, 137.8137.6 (Cquat-Ar); 128.6,
128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6 (CH-Ar);
92.7 (C1); 75.1, 72.8, 72.1 (3 ꢃ CH2-Bn); 79.4, 75.4, 74.6, 71.4 (C2,
C3, C4, and C5); 51.7 (C6).
C0H2-Bn); 50.6, 49.0, 46.7, 46.3 (C2, C7, and C , C0 ); ½a 2D0
= ꢁ29.4
ꢂ
2
7
(c 0.75 CHCl3). HRMS (+ESI): calcd for C35H37O6NNa: 590.2513;
found: 590.2504.
4.1.5. (3R,4R,5R,6R)-N-Benzyloxycarbonyl-3-oxo-4,5,6-
tribenzyloxyazepane (15)
To a solution of (3R,4R,5R,6R)-N-benzyloxycarbonyl-3-hydroxy-
4,5,6-tribenzyloxyazepane 14 (558 mg, 0.98 mmol) in dichloro-
methane (40 mL) were added under nitrogen at room temperature
molecular sieves 4 Å (480 mg) and pyridinium chlorochromate
(636 mg, 2.95 mmol, 3 equiv). The completion of the reaction
was monitored by TLC (cyclohexane/ethyl acetate; 4:1). After 3 h,
the reaction mixture was filtered over CeliteÒ. The filtrate was then
evaporated under reduced pressure. The residue was purified by
flash chromatography (cyclohexane/ethyl acetate; 4:1) to afford
ketone 15 as a pale yellow oil (480 mg, 87%).
4.1.3. (3R,4R,5R,6R)-3-Hydroxy-4,5,6-tribenzyloxyazepane (13)
To a solution of 6-azido-2,3,4-tri-O-benzyl-6-deoxy-D-manno-
pyranoside 12 (570 mg, 1.2 mmol) in tetrahydrofuran (40 mL)
was added palladium on charcoal (350 mg) under nitrogen. The
system was then purged by hydrogen. The reaction mixture was
stirred under hydrogen for 4 h. The completion of the reaction
was monitored by TLC (CH2Cl2/CH3OH; 15:1). The reaction mixture
was filtered over CeliteÒ and evaporated under reduced pressure.
The residue was purified by flash chromatography (CH2Cl2/CH3OH;
30:1 then 15:1) to afford azepane 13 as a colorless oil (400 mg, 85%
yield); 1H NMR (400 M Hz, CDCl3): d 7.38–7.28 (m, 15H, CH-Ar);
4.74 (d, 2J = 11.9 Hz, 1H, Ha of CH2-Bn); 4.73 (d, 2J = 11.6 Hz, 1H,
Ha of CH2-Bn); 4.69 (d, 2J = 11.9 Hz, 1H, Hb of CH2-Bn); 4.64 (d,
2J = 12.1 Hz, 1H, Hb of CH2-Bn); 4.62 (d, 2J = 11.6 Hz, 1H, Hb of
CH2-Bn); 4.60 (d, 2J = 12.1 Hz, 1H, Hb of CH2-Bn); 3.99–3.95 (m,
1H NMR (400 MHz, CDCl
(presence of two rotamers)
3):
d
7.28–7.00 (m, 40H, CH-Ar); 4.95 (d, 2J = 12.3 Hz, 1H, Ha of CH2-
Bn); 4.85 (d, 2J = 12.1 Hz, 1H, Ha0 of CH2-Bn); 4.80 (d, 2J = 12.1 Hz,
1H, Hb of CH2-Bn); 4.68–4.52 (m, 9H, H7a and H07a, Hb0 of CH2-Bn,
3 ꢃ CH2-Bn); 4.90–4.10 (m, 8H, 3 ꢃ CH2-Bn, H3 and H2a); 4.06–
4.00 (m, 1H, H0 ); 3.93–3.86 (m, 5H, H4 and H0 , H5 and H50 , H20 a);
3
4
3.60–3.50 (2d, 2J = 18.8 Hz, 2H, H7b and H70 b); 3.12–3.23 (m, 2H,
H
2b, H02b). 13C NMR (100 MHz, CDCl3): d (presence of two rotamers)
207.4, 206.5 (2 ꢃ C@O ketone); 155.9, 155.4 (2 ꢃ C@O carbamate);
138.3, 138.2, 137.8, 137.7, 136.8, 136.7, 136.3, 136.0 (Cquat-Ar);
128.4, 128.35, 128.3, 128.25, 128.0, 127.95, 127.9, 127.7, 127.65,

J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
647
127.6, 127.4, 127.0 (CH-Ar); 83.6, 83.3 (C5 and C0 ); 75.7, 75.4, 75.0,
137.8 (Cquat-Ar); 136.5 (Cquat); 128.6, 128.5, 128.45, 128.4, 128.2,
5
(C3 and C0 , C4, and C0 ); 73.3, 73.1, 73.0, 72.5, 72.1, 71.8 (3 ꢃ CH2-
128.0, 127.8, 127.75, 127.7, 127.6, 127.5 (CH-Ar); 80.8, 80.7 (C0
3
4
4
Bn + 3 ꢃ C0H2-Bn); 67.5, 67.4 (CH2-Bn and C0H2-Bn); 57.0, 56.8 (C7
and C4); 78.5, 76.8 (C5 and (C0 ); 76.2, 75.1 (C3 and (C03); 73.1,
5
and C0 ); 46.3, 45.7 (C2 and C20 ). ½a 2D0
ꢂ
= ꢁ1.4 (c 0.12 CHCl3). HRMS
72.8 (CH2-Bn and C0H2-Bn); 72.2, 72.0, 71.8, 71.7 (2 ꢃ CH2-Bn and
7
(+ESI): calcd for C35H35O6NNa: 588.2357; found: 588.2353.
2 ꢃ C0H2-Bn); 67.5, 67.2 (CH2-Bn and C0H2-Bn); 63.9, 61.6 (CH2OH
and C0H2OH); 46.9, 46.1 (C7 and (C0 ); 45.6, 45.5 (C6 and (C06);
7
4.1.6. (3R,4R,5R)-N-Benzyloxycarbonyl-3-methylene-4,5,6-
tribenzyloxyazepane (16)
45.5, 42.6 (C2 and (C02). ½a D20
ꢂ
= ꢁ27.0 (c 0.6 CHCl3). HRMS (+ESI):
calcd for C36H39O6NNa: 604.2670; found: 604.22662.
To a cooled solution of methyltriphenylphosphonium bromide
(560 mg, 1.6 mmol, 10 equiv) in THF (5 mL) at ꢁ10 °C was drop-
4.2.2. (3S,4R,5R,6R)-N-Benzyloxycarbonyl-3-hydroxymethyl-
4,5,5-tribenzyloxyazepane (17b)
wise added n-BuLi (570 lL, 1.4 mmol, 9 equiv) and the reaction
mixture was stirred at ꢁ10 °C for 30 min. Then the ylide solution
was added to a cooled solution of (3R,4R,5R,6R)-N-benzyloxycar-
bonyl-3-oxo-4,5,6-tribenzyloxyazepane 15 (90 mg, 0.16 mmol) in
THF (2.5 mL). The reaction mixture was stirred at room tempera-
ture for 16 h, quenched with water and diluted with diethyl ether.
The aqueous layer was extracted with diethyl ether and the com-
bined organic layers were washed with brine, dried over magne-
sium sulfate, filtered and evaporated under reduced pressure.
The crude product was purified by flash chromatography to afford
1H NMR (400 MHz, CDCl3): d (presence of two rotamers)
7.28–7.15 (m, 40H, CH-Ar); 5.15–4.25 (m, 16H, 8 ꢃ CH2-Bn);
4.10–4.05 (m, 4H, H4, (H0 , H5 and (H0 ); 4.00–3.95 (m, 4H, H2a
,
4
5
(H02a, H6 and H7a); 3.84–3.73 (m, 2H, H3 and Ha of CH2OH); 3.70–
3.65 (m, 4H, H03, H70 a, 2H0 of CH2OH); 3.47–3.41 (m, 1H, Hb of
CH2OH); 3.40–3.22 (m, 3H, H2b, H0 , H0 ); 2.36–2.28 (m, 2H, H7b
2b
6
and H07b); 1.50 (s, 2H, 2 ꢃ OH). 13C NMR (100 MHz, CDCl3): d (pres-
ence of two rotamers) 157.4 (2 ꢃ C@O carbamate); 138.1, 138.0,
137.9, 137.8 (Cquat-Ar); 136.6 (Cquat); 128.6, 128.5, 128.45, 128.4,
128.0, 127.8, 127.75, 127.7, 127.6, 127.5 (CH-Ar); 81.8, 81.7 (C4
and C0 ); 76.5, 75.8 (C5 and C0 ); 75.2, 74.1 (C3 and C03); 72.1, 71.8
exoalkene 16 as
a
colorless oil (45 mg, 50% yield).1H NMR
(400 MHz, CDCl3): d (presence of two rotamers) 7.28–6.66 (m,
4
5
40H, CH-Ar); 5.23 (m, 1H, H-alkene); 5.15 (m, 1H, H-alkene);
(CH2-Bn and C0H2-Bn); 71.2, 71.0, 70.8, 70.7 (2 ꢃ CH2-Bn and
2
5.01–5.04 (d and m, J = 12.4 Hz, 3H, 2H0-alkene and Ha of CH2-
2 ꢃ C0H2-Bn); 66.5, 65.2 (CH2-Bn and C0H2-Bn); 62.9, 60.6 (CH2OH
Bn); 4.91 (s, 2H, CH2-Bn); 4.79–4.63 (4d, 2J = 12.4 Hz, 4H,
2 ꢃ CH2-Bn); 4.50–4.47 (m, 5H, H7a and 2 ꢃ CH2-Bn); 4.45–4.37
and C0H2OH); 48.9, 47.1 (C7 and C0 ); 46.6, 44.5 (C5 and C06); 42.5,
7
40.6 (C2 and C02).½a D20
ꢂ
= ꢁ23.0 (c 0.3 CHCl3). HRMS (+ESI): calcd
(2d, 2J = 12.2 Hz and 10.2 Hz, 4H, H7b, H0 and CH2-Bn); 4.28 (d,
for C36H39O6NNa: 604.2670; found: 604.2661.
7a
2J = 12.2 Hz, 1H, Hb of CH2-Bn); 3.93–3.85 (m, 5H, H3 and H0 , H4
3
and H0 , H2a); 3.79–3.70 (m, 3H, H0 , H2b, H70 b); 3.30–3.23 (m, 1H,
4.3. General procedure for the selective reduction of (16)
4
2a
H02b). 13C NMR (100 MHz, CDCl3): d (presence of two rotamers)
141.2, 141.1 (2 ꢃ C@O carbamate); 138.9, 138.8, 138.7, 138.6,
138.1, 138.0, 136.8 (Cquat-Ar); 130.0 (Cquat); 128.9, 128.8, 128.4,
128.35, 128.3, 128.2, 128.0, 127.75, 127.7, 127.65, 127.6, 127.5,
127.45, 127.4, 127.3, 126.9 (CH-Ar); 118.9118.6 (@CH2–alkene);
80.8 (C5 and C0 ); 78.2, 77.8 (C3 and C0 ); 76.7, 76.5 (C4 and C04);
Tris(triphenylphosphine)-rhodium
0.05 mmol) was added to a solution of (3R,4R,5R)-N-benzyloxycar-
bonyl-3-methylene-4,5,6-tribenzyloxyazepane 16 (60 mg,
0.11 mmol) in methanol (2 mL)/ethyl acetate (1 mL). The reaction
mixture was purged from air and stirred under hydrogen atmo-
sphere for 5 h. The completion of the reaction was monitored by
TLC. The solvents were evaporated and the residue was purified
by flash chromatography (toluene/ethyl acetate; 20:1) to afford
the two methyl derivatives (18a: 30 mg; 18b: 15 mg; 75% yield).
(I)
chloride
(50 mg,
5
3
73.2, 73.1 (CH2-Bn); 71.7, 71.5 (CH2-Bn); 70.6, 70.3 (CH2-Bn);
67.2, 67.0 (CH2-Bn and C0H2-Bn); 50.3, 50.1 (C7 and C0 ); 44.9 (C2
7
and C02).
½
a 2D0
ꢂ
= ꢁ3.0 (c 0.09 CHCl3). HRMS (+ESI): calcd for
C36H37O5NNa: 586.2563; found: 586.2555.
4.2. General procedure for the hydroboration of (16)
4.3.1. (3S,4R,5R,6R)-N-Benzyloxycarbonyl-3-methyl-4,5,6-
tribenzyloxyazepane (18a)
To cooled solution of (3R,4R,5R)-N-benzyloxycarbonyl-3-
a
1H NMR (400 MHz, CDCl3): d (presence of two rotamers) (m,
40H, CH-Ar); 5.18–5.08 (m, 4H, 2 ꢃ CH2-Bn); 4.81–4.42 (m, 12H,
3 ꢃ CH2-Bn); 4.22–4.18 (dd, J = 13.5 Hz and 4.5 Hz, H2a); 4.07–
methylene-4,5,6-tribenzyloxyazepane 16 (42 mg, 0.075 mmol) in
THF (1.5 mL) at 0 °C was added the borane–THF complex
(4 ꢃ 340
stirred at room temperature for 4 h. The colorless solution was oxi-
dized and hydrolyzed by addition of ethanol (150 L), an aqueous
solution of hydroxide sodium (2 M, 200 L) and hydrogen peroxide
(200 L). The reaction mixture was diluted in diethyl ether. The or-
lL, 1.36 mmol) by portions. The reaction mixture was
4.03 (dd, J = 7.8 Hz and 5.0 Hz, 1H, H02a); 4.01–3.96 (m, 4H, H3, H0 ,
3
H4, H0 ); 3.78–3.74 (dd, J = 14.0 Hz and 4.1 Hz, 1H, H70 a); 3.68–3.64
4
l
(dd, J = 14.6 Hz and 3.6 Hz, 1H, H07a); 3.55–3.50 (2dd, J = 8.7 Hz
and 6.3 Hz, 2H, H5 a0nd H05); 3.45–3.34 (2dd, J = 13.6 Hz and
8.0 Hz, 2H, H2b and H2b); 3.17–3.09 (2dd, J = 10.8 Hz and 8.0 Hz,
l
l
ganic layer was successively washed with HCl (1 M), water and
brine, dried over magnesium sulfate, filtered and concentrated.
The residue was purified by flash chromatography (cyclohexane/
ethyl acetate; 8:1) to afford the twohydroxymethyl derivatives
17a and 17b (major isomer: 14 mg; minor isomer 7 mg; 50% yield).
2H, H7b and H07b); 2.25–2.20 (m, 1H, H6); 2.06–2.02 (m, 1H, H0 );
6
1.06 (d, 3J = 7.1 Hz, 3H, CH3 ); 1.01 (d, 3J = 7.1 Hz, 3H, CH03). 13C
NMR (100 MHz, CDCl3 ): d (presence of two rotamers) 155.9,
155.6 (2 ꢃ C@O carbamate); 138.7, 138.55, 138.5, 138.45, 138.4
(Cquat-Ar); 137.0, 136.9 (2 ꢃ Cquat); 128.3, 128.2, 127.85, 127.8,
127.7, 127.65, 127.6, 127.5, 127.4 (CH-Ar); 82.6, 82.4 (C5 and C0 );
5
4.2.1. (3R,4R,5R,6R)-N-Benzyloxycarbonyl-3-hydroxymethyl-
4,5,5-tribenzyloxyazepane (17a)
82.1, 82.0 (C3 and C0 ); 76.7, 76.5 (C4 and C04); 73.6, 73.5, 72.3,
3
72.0, 71.8, 72.9 (6 ꢃ CH2-Bn); 67.0, 66.9 (2 ꢃ CH2-Bn); 49.9, 49.2
1H NMR (400 MHz, CDCl3): d (presence of two rotamers)
7.28–7.15 (m, 40H, CH-Ar); 4.92–4.39 (m, 16H, 8 ꢃ CH2-Bn);
(C7 and C0 ); 46.8 and 46.6 (C2 and C0 ); 37.3, 38.8 (C6 and C06);
7
2
18.5 (CH3 and CH0 ).½a D20
ꢂ
= ꢁ17.3 (c 0.6 CHCl3). HRMS (+ESI): calcd
3
4.03–3.92 (m, 4H, H3, H0 , H5 and H0 ); 3.86–3.74 (m, 4H, H2a, H0
,
2a
for C36H39O5NNa: 588.2720; found: 588.2707.
3
5
H6 and H7a); 3.72–3.69 (m, 2H, H3 and Ha of CH2OH); 3.62–3.50
(m, 4H, H03, H70 a, 2H0 of CH2OH); 3.46–3.36 (m, 1H, Hb of CH2OH);
3.35–3.32 (m, 3H, H2b, H0 , H0 ); 2.31–2.16 (m, 2H, H7b and H70 b);
1.50 (s, 2H, 2 ꢃ OH).13C NMR (100 MHz, CDCl3): d (presence of
two rotamers) 157.4 (2 ꢃ C@O carbamate); 138.1, 138.0, 137.9,
4.3.2. (3R,4R,5R,6R)-N-Benzyloxycarbonyl-3-methyl-4,5,6-
tribenzyloxyazepane (18b)
2b
6
1H NMR (400 MHz, CDCl3): d presence of two rotamers) 7.50–
7.21 (m, 40H, CH-Ar); 5.18–4.22 (m, 16H, 8 ꢃ CH2-Bn); 4.04–3.86

648
J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
(m, 4H, H3, H4, H0 and H0 ); 3.80–3.72 (m, 2H, H2a and H2b); 3.70–
References
3
4
3.64 (m, 1H, H02a); 3.60–3.55 (m, 1H, H20 b); 3.47–3.42 (2dd,
J = 5.3 Hz and 1.9 Hz, 2H, H5 and H0 ); 3.36–3.30 (m, 2H, H7a and
H07a); 3.22–3.16 (m, 2H, H7b and H705b); 2.43–2.39 (m, 2H, H6 and
H06); 0.98 (d, 3J = 7.1 Hz, 3H, CH3); 0.91 (d, 3J = 7.1 Hz, 3H, CH03).
13C NMR (100 MHz, CDCl3): d (presence of two rotamers) 155.9,
155.6 (2 ꢃ C@O carbamate); 138.7, 138.55, 138.5, 138.45, 138.4
(Cquat-Ar); 137.0, 136.9 (2 ꢃ Cquat); 128.3, 128.1, 128.0, 127.85,
127.8, 127.7, 127.65, 127.6, 127.5, 127.4 (CH-Ar); 80.4, 79.9 (C5
and C0 ); 77.8, 77.6 (C3 and C0 ); 76.9, 76.6 (C4 and C04); 73.7, 73.5,
1. van der Spoel, A. C.; Jeyakumar, M.; Butters, T. D.; Charlton, H. M.; Moore, H. D.;
Dwek, R. A.; Platt, F. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 17173; Asano, N.
Glycobiology 2003, 13, 93R.
2. (a) Stütz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond;
Wiley-VCH: Weinheim, 1999; (b) Martin, O. R.; Compain, P. Iminosugars: From
Synthesis to Therapeutic Applications; Wiley-VCH: Weinheim, 2007.
3. (a) Mitrakou, A.; Tountas, N.; Raptis, A. E.; Bauer, R. J.; Schulz, H.; Raptis, S. A.
Diabet. Med. 1998, 15, 657; (b) Martin, O. R. Ann. Pharm. Fr. 2007, 65, 5.
4. (a) Groopman, J. E. Rev. Infect. Dis. 1990, 12, 908; (b) Robina, I.; Moreno-Vargas,
A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab. 2004, 5, 329.
5. (a) Laver, W. G.; Bischofberger, N.; Webster, R. G. Sci. Am. 1999, 280, 78; (b)
Dwek, R. A. Virology 2002, 76, 3596; (c) Block, T. M.; Jordan, R. Antiviral Chem.
Chemother. 2002, 12, 317; (d) Greimel, P.; Spreitz, J.; Stütz, A. E.; Wrodnigg, T.
M. Curr. Top. Med. Chem. 2003, 3, 513; (e) Sorbera, L. A.; Castanez, J.; García-
Capdevila, L. Drugs Future 2005, 30, 545; (f) Nash, R. J.; Carroll, M. W.; Watson,
A. A.; Fleet, G. W.J.; Horn, G. PCT Int. Appl. 2007; Chem. Abstr. 2007, 146,
177231.
5
3
73.4, 73.3, 73.0, 71.2 (6 ꢃ CH2-Bn); 67.0, 66.8 (2 ꢃ CH2-Bn); 46.8
(C7 and C0 ); 44.1, 43.7 (C2 and C0 ); 32.6, 31.8 (C6 and C06); 17.4,
7
2
16.9 (CH3 and CH0 ). ½a D20
ꢂ
= ꢁ12.4 (c 0.25 CHCl3). HRMS (+ESI): calcd
3
for C36H39O5NNa: 588.2720; found: 588.2705.
6. (a) Zitzmann, N.; Mehta, A. S.; Carrouée, S.; Butters, T. D.; Platt, F. M.; McCauley,
J.; Blumberg, B. S.; Dwek, R. A.; Block, T. M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
11878; (b) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575; (c) Fiaux, H.;
Popowycz, F.; Favre, S.; Schütz, C.; Vogel, P.; Gerber-Lemaire, S.; Juillerat-
Jeanneret, L. J. Med. Chem. 2005, 48, 4237.
7. Winchester, B.; Vellodi, A.; Young, E. Biochem. Soc. Trans. 2000, 28, 150.
8. Cox, T.; Lachmann, R.; Hollak, C.; Aerts, J.; van Weely, S.; Hrebicek, M.; Platt, F.;
Butters, T.; Dwek, R.; Moyses, C.; Gow, I.; Elstein, D.; Zimran, A. Lancet 2000,
355, 1481; Scott, L. J.; Spencer, C. M. Drugs 2000, 59, 521.
4.4. General procedure for the deprotection of (17) and (18)
To a solution of substrate in methanol in presence of HCl was
added palladium on charcoal (10%). The mixture was purged from
air and stirred under hydrogen atmosphere overnight. The reaction
mixture was filtered through a Celite pad and the solvent was
evaporated under vacuum to afford the hydrochloride salt.
9. (a) Li, H.; Blériot, Y.; Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.;
Rodriguez-Garcia, E.; Vogel, P.; Jimenez-Barbero, J.; Sinaÿ, P. Org. Biomol. Chem.
2004, 2, 1492; (b) Li, H.; Blériot, Y.; Mallet, J.-M.; Zhang, Y.; Rodriguez-Garcia,
E.; Vogel, P.; Mari, S.; Jiménez-Barbero, J.; Sinaÿ, P. Heterocycles 2004, 64, 65; (c)
Martinez-Mayorga, K.; Medina-Franco, J. L.; Mari, S.; Canada, F. J.; Rodriguez-
Garcia, E.; Vogel, P.; Li, H.; Blériot, Y.; Sinaÿ, P.; Jimenez-Barbero, J. Eur. J. Org.
Chem. 2004, 20, 4119; (d) Li, H.; Blériot, Y.; Mallet, J.-M.; Rodriguez-Garcia, E.;
Vogel, P.; Zhang, Y.; Sinaÿ, P. Tetrahedron: Asymmetry 2005, 16, 313; (e) Li, H.;
Schütz, C.; Favre, S.; Zhang, Y.; Vogel, P.; Sinaÿ, P.; Blériot, Y. Org. Biomol. Chem.
2006, 4, 1653; (f) Li, H.; Marcelo, F.; Bello, C.; Vogel, P.; Butters, T. D.; Sollogoub,
M.; Rauter, A. P.; Blériot, Y. Bioorg. Med. Chem. 2009, 17, 5598.
4.4.1. (3R,4R,5R,6R)-3-Hydroxymethyl-4,5,6-trihydroxyazepane
(7)
1H NMR (400 MHz, D2O): d 4.35–4.32 (dt, 3J = 7.1 Hz, 1.8 Hz, 1H,
H6); 3.89–3.85 (dd, 3J = 11.4 Hz and 3.8 Hz, 1H, H5); 3.77–3.70 (m,
3H, H4 and CH2OH); 3.50–3.43 (m, 2H, H7); 3.29–3.38 (m, 2H, H1);
2.05–1.95 (m, 1H, H2). 13C NMR (100 MHz, D2O): d 40.5 (C2); 44.1
(C2); 44.6 (C7); 61.2 (CH2OH); 66.7 (C6); 70.9 (C4); 77.2 (C
5).½a 2D0
ꢂ
= +18.0 (c 0.4 CH3OH). HRMS (+ESI): calcd for C7H16O4N:
10. For pentahydroxylated azepanes see: (a) Martin, O. R. In Carbohydrate Mimics:
Concepts and Methods, Chapleur, Y. Wiley-VCH: New-York, 1997; p 259; (b)
Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; Prakash Reddy, J. J. Org. Chem.
2004, 69, 4760; Jadhav, V. H.; Bande, O. P.; Puranik, V. G.; Dhavale, D. D.
Tetrahedron: Asymmetry 2010, 21, 163.; For tetrahydroxylated azepanes see: (a)
Dax, R.; Gaigg, B.; Grassberger, B.; Koelblinger, B.; Stütz, A. E. J. Carbohydr.
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Bioorg. Med. Chem. 1996, 4, 2055; (e) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.;
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Johnson, H. A.; Thomas, N. R. Bioorg. Med. Chem. Chem. Lett. 2002, 12, 237; (g)
Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.; Wang, P. G. Tetrahedron
Lett. 2002, 43, 6525; (h) Joseph, C. C.; Regeling, H.; Zwanenburg, B.; Chittenden,
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M. A.; Repetto, G.; Sayago, F. J. Tetrahedron: Asymmetry 2002, 13, 1743; (j)
Painter, G. F.; Eldridge, P. G. Falshaw, A. Bioorg. Med. Chem. 2004, 12, 225; Lin,
C.-C.; Pan, Y.-S.; Patkar, L. N.; Lin, H.-M.; Tzou, D.-L. M.; Subramanian, T.; Lin, C.-
C. Bioorg. Med. Chem. 2004, 12, 3259.; For trihydroxylated azepanes, see: (a)
Andersen, S. M.; Ekhart, C.; Lundt, I.; Stütz, A. E. Carbohydr. Res. 2000, 326, 22;
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178.1079; found: 178.1083.
4.4.2. (3S,4R,5R,6R)-3-Hydroxymethyl-4,5,6-trihydroxyazepane
(8)
1H NMR (400 MHz, D2O): d 4.16–4.12 (ddd, 3J = 9.2, 2.8 and
2.0 Hz, 1H, H6); 3.90–3.86 (m, 1H, H5); 3.75–3.67 (m, 3H, H7a and
CH2OH); 3.61–3.57 (dd, 3J = 11.2 and 7.6 Hz, 1H, H4); 3.51–3.46
(m, 1H, H7b); 3.27–3.22 (m, 2H, H2); 2.55–2.45 (m, 1H, H3). 13C
NMR (100 MHz, D2O): d 37.1 (C5); 41.5 (C6); 44.4 (C1); 61.4
(CH2OH); 65.9 (C2); 69.6 (C4); 74.3 (C3).½a D20
= ꢁ26.0 (c 0.2 CH3OH).
ꢂ
HRMS (+ESI): calcd for C7H16O4N: 178.1079; found: 178.1075.
4.4.3. (3S,4R,5R,6R)-4,5,6-Trihydroxy-3-methylazepane (9)
1H NMR (400 MHz, D2O): d 4.33–4.31 (dt, 3J = 6.8 Hz and 2.0 Hz,
1H, H6); 3.66–3.63 (dd, 3J = 8.2 Hz and 2.4 Hz, 1H, H5); 4.50–4.47
(m, 1H, H7a); 3.43 (dd, 3J = 6.8 and 6.0 Hz, 1H, H4); 3.33–3.29 (m,
1H, H7b); 3.29–3.26 (m, 2H, H2); 2.01–1.95 (m, 1H, H3); 1.06 (d,
3J = 7.2 Hz, 3H, CH3).13C NMR (100 MHz, D2O): d 77.2 (C5); 75.0
(C4); 66.6 (C6); 47.3 (C7); 44.1 (C3); 32.9 (C2); 16.1 (CH3).
½
a 2D0
ꢂ
= ꢁ18.8 (c 0.9 CH3OH). HRMS (+ESI): calcd for C7H16O3N:
162.1125; found: 162.1128.
11. (a) Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. Nippon Nogei Kagaku Kaishi 1976,
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4.4.4. (3R, 4R, 5R, 6R)-4,5,6-Trihydroxy-3-methylazepane (10)
1H NMR (400 MHz, D2O): d 4.22–4.18 (ddd, 3J = 8.2 Hz, 2.9 Hz
and 2.0 Hz, 1H, H6); 3.94 (dd, 3J = 5.1 Hz and 2.0 Hz, 1H, H5); 3.76
(dd, 3J = 5.2 Hz and 2.0 Hz, 1H, H4); 3.40–2.99 (m, 4H, H2 and
H7); 2.40–2.35 (m, 1H, H3); 0.98 (d, 3J = 7.2 Hz, 3H, CH3). 13C
NMR (100 MHz, D2O): d 74.7 (C5); 73.1 (C4); 65.9 (C6); 44.5 and
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45.3 (C2 and C7); 29.9 (C3); 16.0 (CH3).½a D20
ꢂ
= 20.8 (c0.4 CH3OH).
HRMS (+ESI): calcd for C7H16O3N: 162.1125; found: 162.1124.
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Acknowledgment
We thank Cintia Volpato for her contribution to this project.

J. Deschamp et al. / Bioorg. Med. Chem. 20 (2012) 641–649
649
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