Stereoselective syntheses of polyhydroxylated azepane derivatives from sugar-based epoxyamides. Part 1: Synthesis from d-mannose

Article abstract of DOI:10.1016/j.tetasy.2010.06.035

An approach to the synthesis of polyhydroxyazepane derivatives from sugar-based epoxyamides or epoxyalcohols, in which the total regioselective epoxide opening by nitrogen nucleophiles is the key step, is described. Thus, novel polyhydroxyazepane carboxamides and aminomethyl polyhydroxyazepanes, with potential pharmacological interest, are synthesized from diacetone d-mannose. Configurational assignments of the obtained products were determined.

Full text of DOI:10.1016/j.tetasy.2010.06.035

Tetrahedron: Asymmetry 21 (2010) 2092–2099
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective syntheses of polyhydroxylated azepane derivatives
from sugar-based epoxyamides. Part 1: synthesis from D-mannose
Noe Oña a, Antonio Romero a, Carmen Assiego a, Claudia Bello b, Pierre Vogel b, M. Soledad Pino-González a,
*
a Departamento de Química Orgánica, Facultad de Ciencias. Universidad de Málaga, 29071 Málaga, Spain
b Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale (EPFL) Batochime 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:
An approach to the synthesis of polyhydroxyazepane derivatives from sugar-based epoxyamides or epox-
yalcohols, in which the total regioselective epoxide opening by nitrogen nucleophiles is the key step, is
described. Thus, novel polyhydroxyazepane carboxamides and aminomethyl polyhydroxyazepanes, with
Received 25 May 2010
Accepted 26 June 2010
Available online 23 July 2010
potential pharmacological interest, are synthesized from diacetone
ments of the obtained products were determined.
D-mannose. Configurational assign-
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2,3-epoxyamides,10 and their regioselective ring-opening reactions
have not been widely investigated. In our laboratory, we studied
the optimal conditions in order to provide 2-[N]-substituted 3-
hydroxyamides with total regioselectivity.9a–d With this type of
intermediates in hand and the adequate hydroxylated chain, we
could obtain the desired azepanes derivatives. Thus, previous expe-
riences carried out with ribose derivatives permitted us to synthe-
size new polyhydroxyazepanes derivatives but in low yield.9a
With the aim of obtaining new and more potent inhibitors with
an azepane ring, we prepared a similar route but starting from dial-
dehyde sugars (Scheme 1). This methodology would lead to poly-
hydroxyazepanes type I, II or III, as promising drug candidates.
Some of them can mimic iminosugar C-glycosides, which have be-
come an important class of iminosugars with promising biological
and therapeutic properties.11 To date, the potential inhibition of
azepane carboxamides has not been described, but their six-mem-
bered analogues, pipecolic acid amides, hold great promise for the
construction of pharmacologically active agents.12 Analogously,
the 6-aminomethylpolyhydroxy-azepanes are products which, to
the best of our knowledge, have not been published, but their pyr-
rolidine13 and piperidine14 analogues have been well documented
and show good profiles as inhibitors of glycosidases.
Nitrogen-containing sugar analogues, known as iminoalditols or
iminosugars, have attracted considerable attention from synthetic
and medicinal chemists, biologists and clinical researchers due to
their potential ability to inhibit glycosidases and glycosyl transfer-
ases.1 The design and synthesis of glycosidase inhibitors have fo-
cused mainly on five- and six-membered iminoalditols, which
are considered to mimic the substrate transition states with oxy-
carbenium ion character. Nevertheless, polyhydroxyazepanes or
seven-membered iminoalditols,2 although known since 1967,3 re-
ceived little attention before Wong et al. revealed that tetra-
hydroxyazepanes are promising inhibitors against a broad range
of glycosidases.4 It was suggested that the greater flexibility of
the seven-membered ring, compared to a five- or six-membered
ring, could improve binding to the active site of the enzyme.5 How-
ever to date, 1,6-dideoxy-1,6-iminoalditols have shown only mod-
erate inhibitory activities; the published results emphasize the
difficulty for predicting the inhibition profile in this family of poly-
hydroxyazepanes.6 All these facts have stimulated a growing inter-
est in developing strategies for synthesizing new derivatives,
including bicyclic compounds.7
Several syntheses of polyhydroxyazepanes start from carbohy-
dratederivatives, takingadvantageoftheirstereocenters.8 However,
anumberofthesesynthesessufferfromlengthyproceduresandnew
strategies have to be considered. In connection with our interest in
the synthesis of epoxyamides derived from carbohydrates, we have
developed a methodology, which has led to iminocompounds with
different ring sizes.9 In these syntheses, the regioselective epoxide
opening by nitrogen nucleophiles is the key step. There are few re-
search groups working on efficient syntheses of optically active
Herein, we report the synthesis and biological evaluation of
new polyhydroxylated azepanes with the configuration depicted
in Scheme 1.15 For this purpose, we chose aldehyde 2, obtained
from D-manno compound 1, as starting material, and prepared a
variety of epoxyamides to obtain azido derivatives as precursors
of the diverse target azepanes.
2. Results and discussion
The first step in the preparation of aldehyde 2 was benzylation
of 2,3:5,6-di-O-isopropylidene-D-mannose 1. A mixture of anomers
* Corresponding author.
6a:6b (5.5:1) was obtained, which was separated by column
E-mail address: pino@uma.es (M.S. Pino-González).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.035

N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
2093
H
N
H
H
N
R2NOC
N
R2N
HO
HO
HO
OH
OH
OH
HO
HO
OH
O
HO
type II
HO
type III
OH
OH
type I
R2NOC
HO
[N]
O
O
O
O
O
OP
OP
OP
OP
OP
OP
[N]
PO
PO
PO
dialdehyde sugars
H
N
X
O
O
O
O
O
O
O
O
O
OH
HO
OBn
OH
HO
OH
2
1
3 X = CONR2
4 X = CH2NR2
5 X = CH2OH
Scheme 1.
chromatography. In previous references,16 only the
a-isomer was
O
BnBr, NaH
isolated by crystallization, the b-anomer was not considered, and
as a consequence its data have not been reported. We isolated both
isomers and demonstrated their utility in this synthesis because
they both lead to the same azepane derivative. Selective acid
O
O
THF, TBAI
(5.5:1)
R
O
O
1
R´
6α : R = H, R´ = OBn
6β : R = OBn, R´ = H
hydrolysis of 6
Periodic oxidation of 7
corresponding aldehydes 2
a
or 6b gave diols 7
or 7b, in the presence of SiO2,17 gave the
or 2b which, without further purifica-
a or 7b, respectively (Scheme 2).
a
a
from 6α
from 6β
tion, were reacted with the sulfur ylides. These ylides Me2SCH-
CONR2 (R: Me, Et, Bn) were obtained in situ from their sulfonium
salts (two phases method) and their reactions let us to obtain the
trans epoxyamides 8a, 8b or 8c (a and b series) with complete ste-
reoselectivity. The best result was obtained with the anomer
80 % AcOH
+
HO
HO
O
O
O
O
O
OBn
O
HO
HO
a and
OBn
for R = Me. (Table 1).
7α
7β
The configurational assignment for the epoxide ring in com-
pounds 8 was assumed as trans (J5,6 ꢀ2) and with the absolute con-
figuration 5S,6R, based on previous configurational studies done
for other epoxyamides.18 In order to assign this configuration, we
a) NaIO4.SiO2, CH2Cl2
b) Me2S+CH2CONR2, Cl-
40% aq. NaOH,
carried out the catalytic transfer hydrogenation of 8ca, to obtain
CH2Cl2
O
O
the hemiacetal 9, which was treated with aqueous periodic acid,
following the method previously described.18a The obtained alde-
hyde solution gave a positive specific rotation, confirming the
epoxide configuration as that of 10 (Scheme 3).
R2N
R2N
O
O
OBn
O
O
O
O
O
O
OBn
The regioselective epoxide opening of epoxyamides 8a
gave 2-azido derivatives 11a or 11b , respectively (Scheme 4).
Catalytic hydrogenation of 11a or 11b gave the corresponding
a or 8ba
a
a
8a α: R = Me
8b α: R = Bn
8c α: R = Et
8a β: R = Me
8b β: R = Bn
a
a
azepane carboxamides 12a or 12b. The same sequence of reactions
was followed with the b-series giving the same final products 12a
or 12b from 8ab or 8bb. The b-anomers of epoxy compounds
showed a significantly lower reactivity in the epoxide opening
but azido 11ab or 11bb had similar behaviour with slightly lower
yields. The NMR data for compounds b were clearly distinguishable
Scheme 2.
Deprotection of the isopropylidene group in 12a or 12b with aq.
from the
signal is about 105.5 ppm in the
the b-series. The signals corresponding to C-2 and C-4 are dis-
placed to a higher field in the b compounds. Compounds , d
a
-series NMR data. Thus, in 13C NMR, anomeric carbon
-series and about 102 ppm in
HCl/MeOH gave N,N-dimethyl or N,N-dibenzyl tetrahydroxy aze-
pane carboxamides 3a or 3b. Reduction of the amide group with
the complex BH3–SMe2, followed by acid hydrolysis, gave dimethyl
or dibenzyl amino azepane derivatives 4a or 4b, as the principal
products.
a
a
ppm: C-2 (84.3–84.9), C-4 (78.9–79.8). Compounds b, d ppm: C-2
(79.1–79.7), C-4 (75.9–77.2).

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N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
Table 1
Experimental conditions in the synthesis of epoxyamides
Entry
RCHO
Sulfonium salt (equiv) Me2S+CH2CONR2, Cl
t (min)
Product
8a
8b
8c
8ab
8bb
Yield (%) (two steps)
1
2
3
4
5
2
2
2
a
a
a
1.7, R = Me
1.3, R = Bn
1.2, R = Et
2.0, R = Me
2.0, R = Bn
40
40
60
60
180
a
a
a
82
60
59
59
65
2b
2b
Amounts for 1 mmol of starting diol 7
a
or 7b. The extraction solvent was CH2Cl2.
O
Et2N
Et2NOC
O
O
HCO2NH4
HIO4
H2O
O
O
O
8c α
CHO
Pd/C
OH
MeOH
10
9
positive specific rotation18a
Scheme 3.
O
O
HCl
OH
H
N
OH
O
R2N
HO
R2N
NaN3, DMF
cat. AcOH
8aα: R = Me
8bα: R = Bn
O
O
HCO2NH4
OH
N3
OBn
OBn
Pd/C
O
HCl
MeOH
HO
H
11aα: R = Me
11bα: R = Bn
Δ
R2N
HO
N
MeOH
3a: R = Me
3b: R = Bn
O
HO
O
O
a) BH3.SMe2
THF
HCO2NH4
Pd/C
2HCl
H
N
OH
O
O
R2N
12a: R = Me
12b: R = Bn
R2N
HO
NaN3, DMF
cat. AcOH
O
8aβ: R = Me
8bβ: R = Bn
MeOH
b) HCl
MeOH
Δ
OH
N3
HO
OH
11aβ: R = Me
11bβ: R = Bn
4a: R = Me
4b: R = Bn
Scheme 4.
On the other hand, the reduction of epoxyamides 8b
with Red-AlÒ in THF at 0 °C, followed by treatment with NaBH4
in MeOH, gave epoxy alcohols 13 or 13b (Scheme 5). Epoxide
opening of 13 or 13b with NaN3 gave, in a totally regioselective
fashion, the azido derivatives 14 or 14b, respectively. Both com-
pounds 14 and 14b gave the same azepane 15 by reduction with
ammonium formate in the presence of 10% Pd/C. Hydrolysis of the
isopropylidene group in compound 15, with hydrochloric acid in
methanol, gave the deprotected azepane 5 as its hydrochloride salt.
a
or 8bb
glycosidases were inhibited by 3a, 3b, 4a and 5 at 1 mM concentra-
tion and at optimal pH of the enzymes.
a
In the case of 2-(aminomethyl)pyrrolidine-3,4-diols,20 2-(amino-
methyl)-5-(hydroxymethyl)pyrrolidine-3,4-diols21 and conduramine
derivatives22 we had observed that N-alkyl or N-acyl substitution
might generate more selective and more potent glycosidase inhibi-
tors. This was also reported by Wong et al. for 1-(aminomethyl)-1-
a
a
a
deoxy-
showed that 1,6-dideoxy-1,6-iminohexitol 16 with the
configuration, as for our 3,4,5,6-tetrahydroxyazepane derivatives, is
a weak inhibitor of -glucosidase from yeast and of -fucosidase
from bovine kidney, but a good (Ki = 4.6 M) inhibitor of b- -N-
L
-fuconojirimycin.23 In their pioneer work, Wong et al.4
-manno
D
a-D
a-L
3. Inhibitory activities toward glycosidases
l
D
The novel 3,4,5,6-tetrahydroxyazepanes19 3a, 3b, 4a and 5 have
acetylglucosaminidase from Jack bean. The inhibitory activity was
reduced significantly, in this case, upon N-benzylation, but improved
been assayed for their inhibitory activities towards
dase from coffee beans, b- -galactosidase from Escherichia coli
and from Aspergillus orizae, -glucosidase from yeast and from
rice, amyloglucosidase from Aspergillus niger, b- -glucosidase from
almonds, -mannosidase from Jack beans, b- -mannosidase from
snail, b- -xylosidase from A. niger, and towards b- -N-acetylgluco-
a-D-galactosi-
inhibitory activity towards
a-L-fucosidase from bovine kidney
D
(Ki = 23 M) was found. It can be concluded (Table 2) that contrary
l
a
-D
to our initial hopes substitution of 1,6-dideoxy-1,6-iminohexitol 16
to generate derivatives 3a, 3b, 4a and 5 does not enhance the
glycosidase inhibitory activity, but improves the selectivity
towards b-D-N-acetylglucosaminidase for the N,N-dimethyl carboxa-
mido derivative 3a only. In fact, upon substitution at C(6) of
iminohexitol 16 by (6S)-17 or (6R)-(hydroxymethyl) group 5, by
D
a-
D
D
D
D
saminidase from Jack beans and from bovine kidney. Except for 3a
which showed selective inhibition of the two latter enzymes (65%
and 56%, respectively, at 1 mM concentration) none of these twelve

N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
2095
tetrahydroxyazepane-2-carboxamide 3a is a selective albeit modest
inhibitor of b-N-acetylglucosaminidase from Jack bean and from
bovine kidney.
8bα or 8bβ
a) RedAl
toluene, 0 ºC
5. Experimental
5.1. General
b) NaBH4
MeOH, 0 ºC
HO
HO
OH
O
Reactions were monitored by thin layer chromatography (TLC)
on E. Merck silica gel plates (0.25 mm) and visualized using UV
light (254 nm) and/or heating with phosphomolybdic acid/cerium
sulfate(IV)/H2SO4 aq solution. Flash chromatography was per-
formed on E. Merck Silica Gel (60, particle size 0.040–0.063 mm).
NMR spectra were recorded on a Bruker Avance-400 or WP200SY
spectrometers at room temperature. Chemical shifts (ppm) are re-
ported relative to the residual solvent peak. Multiplicities are des-
ignated as: singlet (s), doublet (d), triplet (t), multiplet (m) and br
(broad). Coupling constants J are expressed in hertz units. NMR
assignments were undertaken based on two-dimensional COSY
and gHMQC experiments. IR spectra of the azido compounds
showed the N3 typical band at 2324–2352 cmꢁ1. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. High resolu-
tion mass spectra (HRMS) were recorded with a Micromass Auto-
SpecQ instrument of the University of Granada.
R
R
O
O
O
O
O
NaN3, Me3B
O
N3
DMF, Δ
R´
R´
13α R = H, R´ = OBn
13β R = OBn, R´ = H
14α R = H, R´ = OBn
14β R = OBn, R´ = H
HCO2NH4
Pd/C, MeOH
HCl
H
N
H
HO
HO
HO
HO
N
HCl
OH
O
MeOH
HO
OH
HO
O
5
15
5.2. Benzyl 2,3:5,6-di-O-isopropylidene-
mannofuranose 6 and 6b
a- and -b-D-
a
Scheme 5.
To a cooled solution (0 °C) of 2,3:5,6-di-O-isopropylidene-D-
mannofuranose (1.5 g, 5.76 mmol) and BnBr (2.4 mL, 20 mmol) in
anhyd DMF (7.5 mL) was slowly added NaH (60% mineral oil,
1.2 g, 50 mmol). The reaction is monitored by TLC (1:1, Hex/
AcOEt). After 2 h at 0 °C, the mixture is left at rt for 10 h. Then,
MeOH (15 mL) and toluene (50 mL) were added. The mixture is fil-
tered through Celite and the filtrates washed with aq NaHCO3 and
satd NH4Cl. Organic solvents are evaporated and the residue is
(6R)-(dimethylaminomethyl) 4a, or (6R)-(dibenzylaminomethyl)
group 4b compounds devoid of glycosidase inhibitory activity are
obtained.
4. Conclusion
We have demonstrated the utility of D-mannose-derived epoxya-
purified by column chromatography to afford 6a (1.02 g) and 6b
mides in the synthesis of tetrahydroxylated azepane-2-carbox-
amides and 2-(aminomethyl)-3,4,5,6-tetrahydroxy-azepanes, using
regioselective epoxide ring-opening protocol. The complete selectiv-
ity in the processes and the use of inexpensive and readily available
reagents open up the possibility to scale up these procedures in
order to obtain higher amounts of the intermediate products.
The combination of two reducing agents: Red-AlÒ and NaBH4, has
been shown to be a good choice to obtain epoxyalcohols from
carbohydrate-derived epoxyamides, leading to the preparation of
the corresponding 1,6-dideoxy-1,6-iminoheptitols. With regards to
epoxide ring opening by azides, the better method for epoxyamides
was the combination of NaN3 in DMF with a catalytic amount of
AcOH, while terminal epoxyalcohols were more efficiently opened
with NaN3/Me3B, leading to the exclusive formation of the corre-
sponding 2-azidomethyl analogue. The novel N,N-dimethyl 3,4,5,6-
(0.25 g). Total yield: 63%. NMR data of compound 6b are not de-
scribed in the literature: 1H NMR (CDCl3, 400 MHz, d ppm): 7.31–
7.19 (m, 5H, Ph), 4.84 (m, 1H), 4.68–4.58 (m, 3H), 4.51 (m, 1H),
4.39 (m, 1H), 4.02 (dd, 2H), 3.50 (m, 1H), 1.49 and 1.37 (2s,
2 ꢂ 3H, CMe2) 1.31 and 1.29 (2s, 2 ꢂ 3H, CMe2). 13C NMR (CDCl3,
100 MHz, d ppm): 136.9–127.5 (Ph), 113.3 and 108.8 (2CMe2),
100.9 (C-1), 79.4, 78.8 and 76.8 (C-2, C-3 and C-4), 73.0, 71.1
66.5 (C-5, C-6 and CH2Ph), 26.7, 25.4, 25.0 and 24.8 (2CMe2).
5.3. Benzyl 2,3-O-isopropylidene-b-D-mannofuranose 7b
Compound 6b (442 mg, 1.26 mmol) was dissolved in 80% acetic
acid (50 ml), heated for 3 h (35 °C) and evaporated to dryness. The
residue was purified by column chromatography (AcOEt 100%), to
Table 2
Percentage of inhibition of b-D-N-acetylglucosaminidase from Jack bean at 1 mM concentration of various D-manno-1,6-dideoxy-1,6-iminohexitols derivatives (NI = no inhibition,
NR: not reported)
H
N
H
N
H
N
H
N
O
H
N
S
6
5
R
HO
HO
HO
HO
Me2N
HO
R
Me2N
HO
S
1
6
5
1
2
2
OH
OH
OH
OH
HO
4
3
4
3
OH
HO
HO
HO
HO
OH
OH
OH
OH
HO
OH
4a
5
16
89%
17
NRa
3a
NI
NI
65%
a
This compound is a very weak, but selective inhibitor of a-L
-fucosidase (IC50 = 1.7 mM).15b

2096
N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
obtain compound 7b (265 mg, 80%). Rf: 0.5 (AcOEt 100%) 1H NMR
(CDCl3, 200 MHz, d ppm): 7.40–7.25 (m, 5H, Ph), 4.77–4.91 (m,
4H), 4.16–4.04 (m, 2H), 3.86 (dd, 1H), 3.78–3.67 (m, 2H), 2.48 (s,
2H), 1.56 and 1.37 (2s, 3H, CMe2). 13C NMR (CDCl3, 50 MHz, d
ppm): 136.8–127.4 (Ph), 113.5 (CMe2), 100.8 (C-1), 79.4, 79.1 and
75.9 (C-2, C-3 and C-4), 70.9 and 69.6 (C-5 and CH2Ph), 63.7 (C-
6), 25.3 and 25.0 (CMe2).
complete. The NMR data and positive specific rotation were con-
cordant with those of 10.18a
5.6. Epoxide opening with NaN3 in epoxyamides: N,N-dimethyl-
6-azido-1-O-benzyl-6-deoxy-2,3-O-isopropylidene-
D-glycero-a-
D
-manno-heptofuranuronamide 11a
a
To a solution of epoxyamide 8aa (3.06 g, 8.42 mmol) in DMF
(29.3 mL) were added NaN3 (1.08 g, 16.61 mmol) and AcOH
(0.48 mL). The reaction mixture was heated (95 °C) with stirring
under argon for 2 d and monitored by TLC, after which the reaction
was judged complete. The mixture was eluted with AcOEt and
washed with aq. NH4Cl and then with water. The organic layer
was dried (MgSO4) and solvents evaporated under vacuo. Purifica-
5.4. Typical procedure for epoxyamides
The crude aldehyde obtained from diol 7a (4.45 g, 14.33 mmol)
by periodic oxidation17 was dissolved in dichloromethane (100 mL)
and the sulfonium salt Me2S+CH2CONMe2ꢃCl (4.55 g, 24.8 mmol)
and 40% aq NaOH (50 mL) were added. The reaction mixture was
stirred at room temperature and monitored by TLC. After 40 min,
water (10 mL) was added and the organic phase separated. The
aqueous phase was extracted with dichloromethane (2 ꢂ 15 mL)
and the organic layers were washed with water, dried with sodium
sulfate and evaporated in vacuo to obtain epoxide as a syrup which
tion by column chromatography gave 11aa (2.45 g, 72% yield) as a
colourless solid. Compound 11aa had Rf: 0.3 (2:1, Hex/AcOEt), mp:
129–130 °C.
½
a 1D7
ꢄ
¼ þ101 (c 0.98, CH2Cl2). 1H NMR (CDCl3,
400 MHz, d ppm): 7.30–7.18 (m, 5H, Ph), 5.00 (s, 1H, H-1), 4.85
(dd, 1H, J = 3.8, 5.9, H-3), 4.57 (d, 1H, J = 5.9, H-2), 4.47 and 4.33
(2d, 2 ꢂ 1H, CH2Ph), 4.41 (dd, 1H, J = 3.8, 9.1, H-4), 3.99 (d, 1H,
J = 3.7, H-2), 3.93 (dd, 1H, J = 3.7, 9.1, H-5), 3.07 and 2.93 (2s,
2 ꢂ 3H, NMe2), 1.41 and 1.27 (2s, 2 ꢂ 3H, CMe2), 13C NMR (CDCl3,
100 MHz, d ppm): 169.3 (CO), 136.6–127.5 (Ph), 112.4 [C(CH3)2],
105.2 (C-1), 84.3 (C-2), 80.1 (C-3), 79.3 (C-4), 71.4 (CH2Ph), 68.4
(C-6), 55.5 (C-5), 37.1 and 35.1 (NMe2), 25.7 and 24.3 (CMe2). HRMS
(FAB): m/z 407.1866 [M+H]+ (C19H27N4O6 requires 407.1852).
was purified by column chromatography to afford pure 8a
a
(4.27 g, 82%, two steps). Rf 0.2 (1:1, Hex/AcOEt). ½a D17
¼ þ31
ꢄ
(c 0.52, CH2Cl2). 1H NMR (CDCl3, 400 MHz, ppm): 7.36–7.24
(m, 5H, Ph), 5.08 (s, 1H, H-1), 4.82 (dd, 1H, J = 3.7, 5.9, H-3), 4.66
(d, 1H, J = 5.9, H-2), 4.62 and 49.3 (2d, 2 ꢂ 1H, J = 11.8, CH2Ph),
3.90 (dd, 1H, J = 4.8, 3.76, H-4), 3.62 (d, 1H, J = 2.1, H-6), 3.48
(dd, 1H, J = 2.1, H-5), 3.12 and 2.97 (2s, 2 ꢂ 3H, NMe2) 1.42 and
1.30 (s, 3H, CMe2). 13C NMR (CDCl3, 50 MHz, d ppm): 166.1 (CO),
136.9–127.3 (Ph), 112.3 (CMe2), 105.3 (C-1), 84.6 (C-2), 79.2
(C-3), 78.4 (C-4), 68.8 (CH2Ph), 54.0 (C-5), 51.4 (C-6), 35.8 and
35.0 (NMe2), 25.5 and 24.0 (CMe2). (FAB): m/z 386.1591 [M+Na]+
(C19H25NO6Na requires 386.1579). The same procedure was
5.7. N,N-Dibenzyl 6-azido-1-O-benzyl-6-deoxy-2,3-O-
isopropylidene-D-glycero-a-D-manno-heptofuranuronamide
11ba
To a solution of the epoxyamide 8b
a (0.74 g, 1.43 mmol) in
carried out with 2
a and 2b to obtain 8ba and 8bb (Table 1).
DMF (5 mL) were added NaN3 (0.19 g, 2.92 mmol) and AcOH
(0.08 mL, 1.43 mmol). The reaction mixture was heated (95 °C)
with stirring under argon for 2 d and monitored by TLC, after which
the reaction was judged complete. The mixture was eluted with
AcOEt and washed with aq NH4Cl and then with water. The organic
layer was dried (MgSO4) and solvents evaporated under vacuo.
Epoxyamide 8b
a
had Rf 0.3 (3:1, Hex/AcOEt). ½a D17
¼ þ42 (c 0.82,
ꢄ
CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 7.45–7.12 (m, 15H,
3Ph), 4.99 (s, 1H, H-1), 4.77 (dd, 1H, J = 3.8, 5.4, H-3), 4.76, 4.39,
4.47, 4.43, 4.35 and 4.32 (6d, 6 ꢂ 1H, J = 14.5, 16.6, 11.8, 3CH2Ph),
4.59 (d, 1H, J = 5.4, H-2), 3.77 (dd, 1H, J = 3.8, 5.4, H-4), 3.64 (d,
1H, J = 2.1, H-6), 3.60 (dd, 1H, J = 2.1, 5.4, H-5), 1.33 and 1.24 [2s,
2 ꢂ 3H, 2CMe2]. 13C NMR (CDCl3, 100 MHz, d ppm): 167.3 (CO),
137.1, 136.5, 135.9 and 129–126 (3Ph), 112.9 [CMe2], 105.6 (C-
1), 85.1 (C-2), 79.7 (C-3), 79.1 (C-4), 69.2 (CH2Ph), 54.9 (C-5),
52.2 (C-6) 49.0 and 48.2 (2NCH2), 25.7 and 24.2 [CMe2]. HRMS
(FAB): m/z 516.2385 [M+H]+ (C31H34NO6 requires 516.2386). Com-
Purification by column chromatography gave 11b
a (0.65 g, 81%
yield). Compound 11b
a
had Rf 0.6 (3:1, Hex/AcOEt). ½a D17
¼ ꢁ31
ꢄ
(c 0.86, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 7.32–7.16 (m,
15H, 3Ph), 5.02 (s, 1H), 4.88 (dd, 1H), 4.63–4.49 (m, 6H), 4.44 (d,
1H), 4.27 (d, 1H), 4.15 (dd, 1H), 4.07 (d, 1H), 1.38 (s, 3H, C(CH3)2)
and 1.27 (s, 3H, C(CH3)2). 13C NMR (CDCl3, 100 MHz, d ppm):
169.9 (CO), 136.8–127.0 (Ph), 112.7 [C(CH3)2], 105.5 (C-1), 84.5,
80.3 and 79.8 (C-2, C-3 and C-4), 71.9 and 68.9 (C-5 and CH2Ph),
57.1 (C-6), 49.9 and 47.9 (2NCH2), 25.9 and 24.4 [CMe2]. HRMS
(FAB): m/z 559.2555 [M+H]+ (C31H35N4O6 requires 559.2556).
The same procedure was carried out with 8bb to obtain 11bb.
pound 8bb had Rf 0.4 (1:1, Hex/AcOEt). ½a D17
¼ ꢁ2 (c 1.68, CH2Cl2)
ꢄ
1H NMR (CDCl3, 400 MHz, d ppm). 7.33–7.14 (m, 15H, 3Ph), 5.01
(s, 1H), 4.78–4.74 (m, 2H), 4.66 (d, 1H), 4.59 (d, 1H), 4.45 (t, 2H),
4.34 (dd, 2H), 3.78 (dd, 1H), 3.65 (d, 1H), 3.60 (dd, 1H), 1.33 and
1.24 (2s, 2 ꢂ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 167.2
(CO), 136.8–126.7 (3Ph), 114.1 (CMe2), 100.9 (C-1), 79.7, 79.1 and
75.9 (C-2, C-3 and C-4), 71.0 (CH2Ph), 55.4, 51.9, 48.8 and 47.9
(2NCH2, C-5 and C-6), 25.5 and 25.0 (CMe2). HRMS (FAB): m/z
516.2384 [M+H]+ (C31H34NO6 requires 516.2386).
Compound 11bb had Rf 0.5 (3:1, Hex/AcOEt). ½a D17
¼ þ35 (c 2.2,
ꢄ
CH2Cl2).
1H NMR (CDCl3, 400 MHz, d ppm) 7.33–7.13 (m, 15H, 3Ph),
4.82–4.78 (m, 2H), 4.70 (d, 1H), 4.64 (d, 1H), 4.60 (s, 1H), 4.56
(dd, 1H), 4.52–4.43 (m, 5H), 3.97 (d, 1H), 3.70 (dd, 1H), 1.50 and
1.31 (2s, 2 ꢂ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 170.0
(CO), 137.0–126.7 (3Ph), 113.8 (CMe2), 102.0 (C-1), 79.3, 79.0 and
77.2 (C-2, C-3 and C-4), 72.0 and 71.7 (C-5 and CH2Ph), 56.3
(C-6), 49.8 and 47.7 (2NCH2), 25.6 and 25.0 (CMe2). HRMS (FAB):
m/z 559.2553 [M+H]+ (C31H35N4O6 requires 559.2556).
5.5. Debenzylation of epoxyamide 8c
a and periodic oxidation of
9c: (2R,3R)-N,N-diethyl-3-formyl-2-oxirane carboxamide 10
To a solution of 8ca (620 mg, 1.58 mmol) in MeOH (15 mL)
were added 10% Pd/C (130 mg) and ammonium formate (0.80 g),
and the mixture was refluxed for 3 h. The reaction mixture was fil-
tered through Celite and the filtrate was evaporated and the resi-
due was purified by column chromatography to give crude 9.
Purification by flash column chromatography (AcOEt 100%) gave
pure 9. A portion of hemiacetal 9 (80 mg) was placed in an NMR
tube with D2O and HIO4 (484 mg, 8 equiv). The reaction was mon-
itored by 1H NMR and 13C NMR and after a day, it was judged to be
5.8. N,N-Dimethyl-1,6-dideoxy-1,6-imino-2,3-O-isopropylidene-
D
-glycero-
D
-manno-heptonamide 12a
To a solution of azide 11a
a
(282 mg, 0.69 mmol) in MeOH
(51 mL), were added 10% Pd/C (170 mg) and ammonium formate
(0.76 g, 12.05 mmol), and the mixture was refluxed for 3 d. The

N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
2097
reaction mixture was filtered through Celite, the filtrate evapo-
rated and the residue purified by column chromatography to give
12a as a white solid (147 mg, 77%). Rf: 0.6 (AcOEt), mp: 170 °C
dryness. Then, MeOH (4 mL) and 10% HCl (2 mL) were added with
stirring and left for 3 d, after which the mixture is concentrated
and purified by column chromatography to give amino azepane
4a as a pale yellow solid (81 mg, 94%). XPS (X-ray photoelectron
spectroscopy): C9H22Cl2N2O4 (for 2HCl). Rf: 0.3 (4:1 AcOEt/MeOH);
(dec). ½a 1D7
ꢄ
¼ þ10 (c 1.05, MeOH). 1H NMR (D2O, 400 MHz, d
ppm): 4.30 (m, 2H, H-2,3), 4.08 (br s, 1H, H-5), 3.93 (d, 1H,
J = 9.7), 3.78 (d, 1H, J = 9.7,), 2.95 (m, 2H), 2.98 and 2.79 (2s,
2 ꢂ 3H, NMe2), 1.38 and 1.23 (2s, 2 ꢂ 3H, CMe2). 13C NMR (D2O,
100 MHz, d ppm): 173.6 (CO), 108.1 (CMe2), 76.1, 74.8, 74.6 and
71.9 (C-2, C-3, C-4 and C-5), 56.3 (C-6), 44.8 (C-1), 37.5 and 35.5
(NMe2), 24.9 and 22.5 (CMe2). HRMS (FAB): m/z 275.1528 [M+1]+
(C12H23N2O5 requires 275.1524).
Rf: 0.2 (2:1 AcOEt/MeOH), mp: dec; ½a D17
ꢄ
¼ þ19 (c 1, MeOH). 1H
NMR (CD3OD, 400 MHz, d ppm): 4.18 (d, 1H), 3.98 (dd, J = 10.75,
3.22, 1H), 3.91 (dd, J = 5.37, 1H), 3.87 (dd, J = 5.37, 1H), 3.50 (m,
3H), 3.38 (m, 1H), 3.24 (br s, 3H), 2.78 and 2.77 (2s, NMe2), 2.85
and 2.80 (2 m, 2H), 2.50 (d, J = 13.9). 13C NMR (D2O, 100 MHz, d
ppm): 74.3, 70.7, 67.1 and 66.7 (C-2, C-3, C-4 and C-5), 63.8 (C-
7), 54.2 (C-6), 49.4 (C-1), 48.4 and 47.7 (2NCH3). Compound 4a
(2HCl) was treated with ammonia to give the free amine 4a with
HRMS (FAB): m/z 221.1499 [M+H]+ (C9H21N2O4 requires 221.1501).
5.9. N,N-Dibenzyl-1,6-dideoxy-1,6-imino-2,3-O-isopropylidene-
D
-glycero-D-manno-heptonamide 12b
To a solution of azide 11b
a
(100 mg, 0.179 mmol) in MeOH
5.13. 7-N-Dibenzylamino-1,6,7-trideoxy-1,6-imino-D-glycero-D-
manno-heptitol dichlorhydrate 4b
(15 mL) were added 10% Pd/C (50 mg) and ammonium formate
(0.220 g, 3.49 mmol), and the mixture was refluxed for 2 d. The
reaction mixture was filtered through Celite and the filtrate was
evaporated and the residue purified by column chromatography
to give 12b as a white solid (59 mg, 69%). Rf: 0.64 (AcOEt 100%);
To a solution of azepane 12b (48 mg, 0.11 mmol) in THF (5 mL)
was added BH3ꢃSMe2 (0.10 mL, 1.05 mmol). The reaction mixture
was heated (60 °C) for 1 d, quenched with EtOH and evaporated
to dryness. Then, MeOH (4 mL) and 10% HCl (2 mL) were added
with stirring and left for 3 d, after which the mixture was concen-
trated and purified by column chromatography to give 4b as a yel-
mp: 118 °C. ½a 1D7
ꢄ
¼ ꢁ25 (c 0.93, MeOH). 1H NMR (CDCl3, 400 MHz,
d ppm): 7.35–7.10, (m, 10H, Ph), 4.71 (m, 2H, NCH2Ph), 4.58
(d, 1H, NCH2Ph), 4.31 and 4.20 (2 m, 2 ꢂ 3H), 3.8 (m, 1H), 3.20
and 2.98 (dd and br d, 2 ꢂ 1H, J = 3.2 and 15.6, CH2NH), 1.48 and
1.30 (2s, 2 ꢂ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 173.6
(CO), 136.6–127.1 (Ph), 107.3 [C(CH3)2], 76.8, 75.5, 75.0, 72.5, 58.8
(NCHCO), 49.8 and 47.4 (2NCH2Ph), 46.7 (CH2NH), 26.1 and 23.5
(CMe2). HRMS (FAB): m/z 449.2053 [M+Na]+ (C24H30N2O5Na
requires 449.2052).
lowish syrup (34 mg, 68%). Rf: 0.3 (4:1 AcOEt/MeOH). ½a D20
¼ ꢁ3 (c
ꢄ
0.85, MeOH). 1H NMR (CD3OD, 400 MHz, d ppm): 7.41–7.16 (m,
10H, 2Ph), 4.00–3.72 (m, 3H), 3.46, 3.59 (m, 2H), 3.26 (d, 2H),
2.99–2.50 (m, 2H). 13C NMR (CD3OD, 100 MHz, d ppm): 138.5–
128.8 (Ph), 74.9, 72.4, 69.3 and 67.4 (C-2, C-3, C-4 and C-5), 59.2
(2NCH2), 56.3 and 53.4 (C-6 and C-7), 44.3 (C-1). HRMS (as free
amine): m/z 373.2125 [M+H]+ (C21H29N2O4 requires 373.2127).
5.10. N,N-Dimethyl-1,6-dideoxy-1,6-imino-D-glycero-D-manno-
heptonamide chlorhydrate 3a
5.14. 5,6-Anhydro-1-O-benzyl-2,3-O-isopropylidene-
-manno-heptofuranose 13
D-glycero-
a-
D
a
A solution of azepane 12a (60 mg, 0.22 mmol) in MeOH (4 mL)
with 10% HCl (2 mL) was left for 3 d at rt. The mixture was concen-
trated under vacuo to give 3a as yellowish syrup (59.3 mg, 100%).
A 70% Red-AlÒ solution in toluene (0.21 mL, 0.73 mmol) was
added dropwise to a solution of 8b (339 mg, 0.66 mmol) in THF
Rf: 0.3 (3:2 AcOEt/MeOH). ½a D30
ꢄ
¼ þ9 (c 1.2, MeOH). 1H NMR (D2O,
a
(7.4 mL) at 0 °C. After stirring for 35 min, ethyl acetate was added
followed by a solution of aqueous sodium potassium tartrate and
the mixture was stirred for a further 15 min. The reaction mixture
was extracted with AcOEt, dried over anhydrous MgSO4, concen-
trated under reduced pressure, and then carried to the next step
without purification. Rf: 0.3 (3:1, Hex/AcOEt). The obtained alde-
hyde (yellowish syrup) was dissolved in dry MeOH (5 mL), cooled
at 0 °C and treated with NaBH4 (13 mg, 0.34 mmol). After stirring
for 20 min, the reaction was quenched with several drops of water
and concentrated under reduced pressure. The residue was puri-
400 MHz, d ppm): 4.38 (d, 1H), 4.03 (d, 2H), 3.72 (d, 1H), 3.66 (d,
1H), 3.19 (d, 2H), 2.85 (s, 3H, NCH3), and 2.71 (s, 3H, NCH3). 13C
NMR (D2O, 100 MHz, d ppm): 166.4 (CO), 71.5, 71.1, 68.9 and
64.8 (C-2, C-3, C-4 and C-5), 55.7 (C-6), 43.8 (C-1), 36.7 and 35.4
(2NCH3). HRMS (FAB): (as free amine): m/z 235.1290 [M+1]+
(C9H19N2O5 requires 235.1294).
5.11. N,N-Dibenzyl 1,6-dideoxy-1,6-imino-D-glycero-D-manno-
heptonamide chlorhydrate 3b
fied by column chromatography to give 13
a (168 mg, 80%, two
A solution of azepane 7b (80 mg, 0.187 mmol) in MeOH (4 mL)
with 10% HCl (2 mL) was left for 3 d at rt. The mixture was concen-
trated under vacuo to give 3b as a white solid (79 mg, 100%). Rf: 0.5
steps) as a colourless oil. Rf: 0.2 (2:1, Hex/AcOEt). ½a D21
¼ þ41 (c
ꢄ
1.26, CH2Cl2).1H NMR (CDCl3, 200 MHz, d ppm): 7.44–7.26 (m,
5H, Ph), 5.12 (s, 1H), 4.84 (dd, 1H), 4.69–4.45 (m, 4H), 3.97 (dd,
1H), 3.86 (dd, 1H), 3.70 (dd, 1H), 3.33 (dd, 1H), 3.21 (m, 1H), 1.47
(s, 3H, CMe2) and 1.32 (s, 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d
ppm): 137.1–127.7 (Ph), 112.6 [CMe2], 105.5 (C-1), 84.8, 79.8 and
79.0 (C-2, C-3 and C-4), 69.0 (CH2Ph), 61.3 (C-7), 57.2 and 52.3
(C-5 and C-6), 25.8 and 24.4 [CMe2]. The same procedure was car-
ried out with 8bb to obtain 13b (97%, two steps). Compound 13b
(4:1 AcOEt/MeOH); mp: 60 °C. ½a D28
ꢄ
¼ ꢁ27 (c 1.1, MeOH). 1H NMR
(D2O, 200 MHz, d ppm): 7.24–7.03 (m, 10H, 2Ph), 4.89–4.66 (m,
2H), 4.26 (d, 2H), 4.20–4.02 (m, 2H), 3.92 (d, 1H), 3.76 (dd, 2H),
3.21 (dd, 1H), 2.90 (dd, 1H). 13C NMR (D2O, 50 MHz, d ppm):
169.6 (CO), 136.8–127.9 (Ph), 73.7, 73.6, 70.2 and 66.2 (C-2, C-3,
C-4 and C-5), 56.9 (C-6), 51.7 and 51.2 (2NCH2) and 45.3 (C-1).
HRMS (FAB): (as free amine): m/z 387.1922 [M+H]+ (C21H27N2O5
requires 387.192).
had Rf 0.3 (1:2, Hex/AcOEt). ½a D21
ꢄ
¼ ꢁ37 (c 0.22, CH2Cl2) 1H NMR
(CDCl3, 200 MHz, d ppm): 7.40–7.21 (m, 5H, Ph), 4.95–4.59 (m,
5H), 3.95 (dd, 1H), 3.82 (s, 1H), 3.70–3.51 (m, 2H), 3.39 (dd, 1H),
3.26 (ddd, 1H), 1.57 and 1.37 (2s, 2 ꢂ 3H, CMe2). 13C NMR (CDCl3,
50 MHz, d ppm): 139.4–126.7 (Ph), 113.8 (CMe2), 100.9 (C-1),
79.5, 79.2 and 76.5 (C-2, C-3 and C-4), 70.9 (CH2Ph), 61.2 (C-7),
57.4 and 52.5 (C-5 and C-6), 25.5 and 25.0 (CMe2). HRMS (FAB):
m/z 323.1490 [M+H]+ (C17H23O6 requires 323.1494).
5.12. 7-N-Dimethylamino-1,6,7-trideoxy-1,6-imino-D-glycero-D-
manno-heptitol dichlorhydrate 4a
To a solution of azepane 12a (80 mg, 0.29 mmol) in THF (5 mL)
was added BH3ꢃSMe2 (0.0.28 mL, 2.95 mmol). The reaction mixture
was heated (60 °C) for 1 d, quenched with EtOH and evaporated to

2098
N. Oña et al. / Tetrahedron: Asymmetry 21 (2010) 2092–2099
5.15. 6-Azido-1-O-benzyl-2,3-O-isopropylidene-
D
-glycero-
a
-
D
-
glycoside hydrolyzed/min), pre-incubated for 5 min at 20 °C with
the inhibitor, and increasing concentration of aqueous solution
of the appropriate p-nitrophenyl glycoside substrates buffered to
the optimal pH of the enzyme were incubated for 20 min at
37 °C (45 °C for the amyloglucosidases). The reaction was stopped
by the addition of a 2.5 volume of 0.2 M sodium borate buffer pH
9.8. The p-nitrophenolate formed was quantified at 410 nm.
manno-heptofuranose 14
a
To a stirred solution of 13a (536 mg, 1.66 mmol) in DMF
(16 mL) were added NaN3 (0.20 mg, 3.08 mmol) and Me3B
(0.37 mL, 3.32 mmol). The reaction mixture was heated at 70 °C
and monitored by TLC. After 2 d, aqueous NaHCO3 was added por-
tionwise at 0 °C and the mixture was stirred for 30 min and then
extracted with AcOEt. The combined organic extracts were dried
(anhyd MgSO4) and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (2:1, Hex/
Acknowledgements
This research is supported with funds from the Dirección Gen-
eral de Investigación Científica y Técnica of Spain (CTQ2007-
66518/BQU) and from the Consejería de Educación y Ciencia, Junta
de Andalucia (FQM 158) and by the Swiss National Science Founda-
tion (Bern).
AcOEt), to give 14
a (495 mg, 82%) as a colourless oil. Rf: 0.5 (3:2,
Hex/AcOEt).
½
a 1D9
ꢄ
¼ þ59 (c 1.08, CH2Cl2). 1H NMR (CDCl3,
400 MHz, d ppm): 7.31–7.20 (m, 5H, Ph), 5.07 (s, 1H), 4.83 (dd,
1H), 4.60 (m, 2H), 4.43 (d, 1H), 4.12–4.03 (m, 3H), 3.82 (m, 2H),
3.68 (q, 1H), 3.22 (d, 1H), 1.42 and 1.27 (2s, 2 ꢂ 3H, CMe2). 13C
NMR (CDCl3, 100 MHz, d ppm): 136.8–127.6 (Ph), 112.4 (CMe2),
105.2 (C-1), 84.3, 79.9 and 78.3 (C-2, C-3 and C-4), 70.1, 68.9,
64.7 and 61.7 (CH2Ph, C-5, C-6 and C-7), 25.6 and 24.2 (CMe2).
The same procedure was carried out with 13b to obtain 14b (%).
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5.16. 1,6-Dideoxy-1,6-imino-2,3-O-isopropylidene-D-glycero-D-
manno-heptitol 15
To a stirred solution of 14a (495 mg, 1.36 mmol) in MeOH
(100 mL) were added ammonium formate (1.5 g, 23. 8 mmol) and
10% Pd/C (0.34 g). The reaction mixture was refluxed for 3 d and
then filtered with Celite and concentrated under reduced pressure.
The residue was purified by flash column chromatography (4:1,
Hex/AcOEt), to give 15 (315 mg, 99%) as a colourless oil. Rf: 0.3
(4:1, AcOEt/MeOH). ½a D19
ꢄ
¼ þ4 (c 1.28, MeOH). 1H NMR (D2O,
400 MHz, d ppm): 4.31 (t, 1H), 4.00 (d, 1H), 3.80 (d, 1H), 3.74
(dd, 1H), 3.66 (dd, 1H), 3.35–3.21 (m, 3H), 3.15 (s, 3H), 1.35 [s,
3H, C(CH3)2] and 1.22 (s, 3H, C(CH3)2). 13C NMR (D2O, 100 MHz, d
ppm): 109.0 [C(CH3)2], 75.1, 73.5, 72.1 and 67.7 (C-2, C-3, C-4
and C-5), 59.4 and 58.9 (C-6 and C-7), 43.8 (C-1), 25.2 and 22.9
[C(CH3)2]. HRMS (FAB): m/z 234.1342 [M + H]+ (C10H20NO5 requires
234.1341).
5.17. 1,6-Dideoxy-1,6-imino-D-glycero-D-manno-heptitol
chlorhydrate 5
To a stirred solution of 15 (150 mg, 0.64 mmol) in MeOH (4 mL)
was added a 10% aqueous solution of HCl (2 mL). After 2 d, the
reaction mixture was concentrated under reduced pressure to give
chlorhydrate 5 (147 mg, 100%). Rf: 0.1 (4:1 AcOEt/MeOH). ½a D22
¼
ꢄ
þ2 (c 1.65, MeOH/H2O 1:1). 1H NMR (D2O, 400 MHz, d ppm):
4.04 (m, 1H), 3.94 (m, 1H), 3.80 (m, 1H), 3.73–3.56 (m, 2H) and
3.29–3.01 (m, 4H). 13C NMR (D2O, 100 MHz, d ppm): 69.4, 69.2,
66.9 and 65.4 (C-2, C-3, C-4 and C-5), 58.9 and 58.8 (C-6 and
C-7) and 44.6 (C-1). HRMS (as free amine): m/z 194.1028 [M+H]+
(C7H16NO5 requires 194.1028).
5.18. Glycosidase inhibition assays
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lmol of

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