Studies on the transformation of nitrosugars into iminosugars III: synthesis of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol

Article abstract of DOI:10.1016/j.tetasy.2009.12.006

A divergent synthesis of the two novel polyhydroxylated azepanes (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol from d-mannose is described. The method involves a Henry reaction between dimethyl-tert-butylsilyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside and 2-nitroethanol followed by a reductive ring closure of the resulting epimeric nitro aldols. Glycosidase inhibition tests showed that (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol exhibits a weak but selective inhibition against α-l-fucosides.

Full text of DOI:10.1016/j.tetasy.2009.12.006

Tetrahedron: Asymmetry 21 (2010) 21–26
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies on the transformation of nitrosugars into iminosugars III: synthesis
of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and
(2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol
c
Amalia M. Estévez a, Raquel G. Soengas b, José M. Otero a, Juan C. Estévez a, , Robert J. Nash ,
*
Ramón J. Estévez a,
*
a Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
b Departamento de Química Fundamental, Universidade de A Coruña, Campus de A Zapateira, 15031, A Coruña, Spain
c Phytoquest Limited, IBERS, Plas Gogerddan, Aberystwyth, Ceredigion, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A
divergent synthesis of the two novel polyhydroxylated azepanes (2R,3R,4R,5R,6R)-2-(hydroxy-
methyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol from
-mannose is described. The method involves a Henry reaction between dimethyl-tert-butylsilyl 2,3-O-iso-
propylidene- -lyxo-pentodialdo-1,4-furanoside and 2-nitroethanol followed by a reductive ring closure
of the resulting epimeric nitro aldols. Glycosidase inhibition tests showed that (2R,3R,4R,5R,6S)-2-
(hydroxymethyl)azepane-3,4,5,6-tetraol exhibits a weak but selective inhibition against -fucosides.
Received 12 October 2009
Revised 30 November 2009
Accepted 10 December 2009
Available online 1 February 2010
D
a
-D
a-L
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
cosidases due to them being structurally more flexible than the
corresponding pyrrolidines and piperidines.10,11
With the breakthroughs in glycobiology, glycosidases have re-
ceived considerable attention due to their use as biochemical tools
and involvement in several important biological processes, such as
digestion, the biosynthesis of glycoproteins, and the catabolism of
glycoconjugates. Accordingly, glycosidase inhibitors have been
extensively investigated over the last two decades on account of
their potential as therapeutic agents.1 Indeed, some examples have
already been tested and approved for use in the treatment of var-
ious diseases such as Gaucher’s disease,2 diabetes,3 cancer4, and
viral infections,5 including AIDS.6 This situation has led to a consid-
erable effort in recent years aimed at understanding the structural
types, mechanisms of action, and synthesis of glycosidase
inhibitors.
In 2004, Sinaÿ et al. reported for the first time the preparation and
biological evaluation of a number of 1,6-dideoxy-1,6-iminoheptitols
2, a novel family of polyhydroxylated azepanes that have an extra
hydroxymethyl group compared to the previously reported ana-
logues, so they can be considered as higher homologuesof deoxynoj-
irimycin 1b (Fig. 1).12 Some of these derivatives have shown potent
and specific glycosidase inhibition; for example, compound 2a is a
potent and selective inhibitor of coffee bean
a-galactosidase and
compound 2b strongly inhibits bovine liver b-galactosidase. Further
intensive work in this field by Blériot et al. resulted in the develop-
ment of alternative synthetic routes for the preparation of additional
azepanes 213 and related acetamido tri- and tetra-hydroxyaze-
panes,14 some of which show salientable inhibition properties.
The most prominent glycosidase inhibitors are imino sugars,7
which are polyhydroxylated nitrogen-containing ring skeleton
analogues of furanoses or pyranoses in which the ring oxygen is re-
placed by nitrogen.8 A great deal of synthetic effort has been fo-
cused on the preparation of substituted pyrrolidine or piperidine
mimics of the corresponding sugars, including nojirimycin 1a and
deoxynojirimycin 1b, the former being an imino sugar that can
H
N
H
N
X
HO
HO
HO
R1
R2
R3
R6
R5
HO
OH
OH
R4
be regarded as the result of replacing the ring oxygen of D-glucose
by a nitrogen.9 However, only a few higher homologues such as
azepanes 2 have been reported to date even though, despite the
fact that they could probably adapt better to the active site of gly-
1a: X=OH, 1b: X=H
2a: R1=R3=R5=H, R2=R4=R6=OH
2b: R2=R4=R5=H, R1=R3=R6=OH
2c: R2=R4=R5=H, R2=OBn, R3=NHAc, R6=OH
2d: R1=R4=R6=H, R2=R3=OH, R5=Me
2e: R2=R3=R5=H, R2=R6=OH, R4=NHAc
* Corresponding authors.
E-mail address: ramon.estevez@usc.es (R.J. Estévez).
Figure 1.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.006

22
A. M. Estévez et al. / Tetrahedron: Asymmetry 21 (2010) 21–26
O2N
HO
G2HN
HO
CbzHN
HO
H
N
H
OH
O
OH
O
OH
O
N
HO
HO
HO
HO
v
OG1
OG1
OH
iv
ii
iii
O
OH
i
O
OH
O
O
O
O
O
O
HO
HO
O
9
8
4
7
O
OG1
6 a: G2=H, b: G2=Cbz
H
O2N
HO
G2HN
HO
CbzHN
HO
O
O
OH
O
OH
O
OH
O
H
H
3
i
N
N
HO
HO
HO
HO
v
OG1
OG1
OH
iii
iv
ii
G1=TBDMS
O
OH
O
O
O
O
O
O
O
OH
HO
HO
12
13
5
11
10 a: G2=H, b: G2=Cbz
Scheme 1. Reagents and conditions: (i) NO2CH2CH2OH, NaOMe, MeOH, rt, 4 h (28% of 4 and 31% of 5); (ii) (a) H2, Raney nickel, methanol, rt, 2 h; (b) ClCbz, HNaCO3, EtOAc, rt,
4 h (72% of 6b from 5 and 85% of 10b from 5); (iii) TBAF, THF, rt, 15 h, (100% of 8 from 6b and 94% of 12 from 10b); (iv) NH4COO, Pd black, methanol, AcOH, rt, 12 h then 50 °C,
4 h (97% of 8 from 7 and 95% of 12 from 11); (v) TFA/H2O 1:1, rt, 15 h (100% of 9 from 8 and 98% of 13 from 12).
Azepane 2c displays potent and selective b-N-acetylhexosaminidase
inhibition;14c azepane 2d is a potent b-glucosidase inhibitor14b
while azepane 2e has been shown to inhibit GH84 glycoside hydro-
lases.13b On the other hand, due to the unusual spatial distribution of
the hydroxyl groups,15 these azepanes not only display a different
inhibitionprofile compared tothe previously reportedpolyhydroxy-
latedazepanes, buttheyarealsomorepronetoformhydrogenbonds
with nitrogenated bases, thus improving their ability to bind to the
minor groove of DNA.16
Nitro sugars are powerful synthetic materials because they
combine the synthetic potential of sugars and the chemical versa-
tility of the nitro group.17 The nitroaldol condensation (the Henry
reaction) is a classical method for the construction of carbon–car-
bon bonds. After the carbon framework has been set up, the nitro
group can be converted into a range of other functionalities,
including reduction to an amino group.
As a continuation of our interest in new synthetic applications of
nitrosugars,18,19 and specifically on their utility in the synthesis of
Figure 2. ORTEP diagram of compound 4.
imino sugars,18 we herein report a divergent synthesis of azepanes
9 and 13. This approach involves the early introduction of the 2-
nitroethanol subunit at position C-6 of nitrosugars 4 and 5 by means
of a Henry reaction between compound 3 and formaldehyde
(Scheme 1). This step is followed by the reduction of the respective
nitro groups to amino groups and a heteroannulation protocol previ-
ously used in the synthesis of six-membered iminosugars.20
2. Results and discussion
The starting material used was the D-mannose-derived alde-
hyde 3 which has an orthogonal protecting system designed for
the easy and selective deprotection of the OH at the anomeric po-
sition in an advanced stage of the synthesis. A Henry reaction of
aldehyde 3 with nitroethanol and sodium methoxide as the base
provided a good yield of a 1:1 epimeric mixture of nitrosugars 4
and 5,19g which were isolated after column chromatography, crys-
tallized from ethyl acetate/hexane and unambiguously character-
ized21,22 by means of X-ray experiments (see Fig. 2 and Fig. 3
respectively). In this way it was established that the two com-
pounds are the epimers predicted by the Felkin–Ahn rule. These
compounds have the same configuration at their C-5 positions,
while the nitro group at C-6 has an (R)-configuration in compound
4 (Fig. 2) and an (S)-configuration in compound 5 (Fig. 3).
Figure 3. ORTEP diagram of compound 5.
tected compound with three orthogonal protecting groups
(Scheme 2). Treatment of 6b with TBAF in THF gave hemiacetal 7,
which upon hydrogenation using acetic acid as the solvent and Pd/
C as the catalyst resulted in the expected direct formation of azepane
8, a compound that was finally converted into azepane 9 after the re-
moval of its isopropylidene-protecting group under acidic condi-
tions. Application of this protocol to nitrosugar 5 allowed the
epimeric azepane 13 to be obtained in good yield via compounds
10a, 10b, 11, and 12.
Compounds 4 and 5 were immediately subjected to a reductive
ring closure protocol.23 Hydrogenation of nitrosugar 4 with a Raney
nickel as the catalyst provided an unstable amine 6a, which directly
reacted with benzyl chloroformate to give derivative 6b, a fully pro-

A. M. Estévez et al. / Tetrahedron: Asymmetry 21 (2010) 21–26
23
O
4. Experimental
O
OBn
H
Melting points were determined using a Kofler Thermogerate
apparatus and are uncorrected. Specific rotations were recorded on
a JASCO DIP-370 optical polarimeter. Infrared spectra were recorded
on a MIDAC Prospect-IR spectrophotometer. Nuclear magnetic reso-
nance spectra were recorded on a Bruker DPX-250 apparatus. Mass
spectra were obtained on a Hewlett Packard 5988A mass spectrom-
eter. Elemental analyses were obtained from the Elemental Analysis
Service at the University of Santiago de Compostela. Thin layer chro-
matography (TLC) was performed using Merck GF-254 type 60 Silica
Gel and ethyl acetate/hexane mixtures as eluents; the TLC spots
were visualized with Hanessian mixture. Column chromatography
was carried out using Merck type 9385 silica gel.
O
O
14
O2N
HO
O2N
HO
OH
O
OH
O
OBn
OBn
i
O
O
O
ii
O
16
15
ii
12
8
Scheme 2. Reagents and conditions: (i) NO2CH2CH2OH, NaOMe, MeOH, rt, 4 h (28%
of 15 and 31% of 16); (ii) H2, Raney nickel, methanol, rt, 2 h.
4.1. 1-O-tert-Butyldimethylsilyl-6-deoxy-2,3-di-O-isopropylidene-
6-nitro-
ldimethylsilyl-6-deoxy-2,3-di-O-isopropylidene-6-nitro-
-manno-heptofuranose 5
D
-glycero-
a
-
D
-manno-heptofuranose 4 and 1-O-tert-buty-
L-glycero-
a-D
In order to achieve a shorter and more efficient access to our tar-
gets 9 and 13, the route described in Scheme 2 was designed. This
route started from aldehyde 14, which is similar to compound 3 ex-
cept that its anomeric hydroxyl group is protected as a benzyloxy
derivative in order to satisfy the requirement of orthogonal protec-
tion with respect to hydroxy groups at positions C-2 and C-3.
According to this new route, a Henry reaction of aldehyde 14
with nitroethanol, using sodium methoxide as a base, provided a
4:1 epimeric mixture of nitrosugars 15 and 16, from which the
two epimers were isolated by column chromatography. The abso-
lute stereochemistry of both nitroaldols was readily established
when compound 15 was transformed into azepane 8 and com-
pound 16 into azepane 12. Hydrogenation of nitrosugar 15 using
Pd/C as the catalyst directly provided the previously obtained aze-
pane 8, which is the precursor of 9. Finally, hydrogenation of the
epimeric nitrosugar 16 under the same conditions gave compound
12, the precursor of azepane 13. This modified approach formally
constitutes a second synthesis of azepanes 9 and 13, which were
now obtained in 10% global yield after a five-step sequence. This
route is clearly simpler and more efficient than the synthetic ap-
proach represented in Scheme 1, which led to the same two aze-
panes in 5% global yield in a seven-step sequence.
To a solution of 1-O-tert-butyldimethylsilyl-2,3-O-isopropyli-
dene- -lyxo-pentodialdo-1,4-furanose (3) (0.18 g, 0.60 mmol) in
a-D
dry methanol (5 mL) were added nitroethanol (0.15 mL, 1.81 mmol)
and sodium methoxide (0.09 g, 1.75 mmol) and the resulting mix-
ture was stirred at rt for 4 h. The reaction was neutralized with
DOWEX 50 W resin, filtered, and the filtrate was preabsorbed onto
silica, and purified by flash column chromatography (ethyl ace-
tate/hexane 2:7) to afford 1-O-tert-butyldimethylsilyl-6-deoxy-
2,3-di-O-isopropylidene-6-nitro-
nose 4 (72 mg, 31%) and 1-O-tert-butyldimethylsilyl-6-deoxy-2,3-
di-O-isopropylidene-6-nitro- -glycero- -manno-heptofuranose 5
D-glycero-a-D-manno-heptofura-
L
a-D
(66 mg, 28%). Both isomers were crystallized from ethyl acetate/
hexane. Data for 5. Mp: 129–131 °C; ½a D23
¼ þ30:6 (c 1.0, chloro-
ꢀ
form); 1H NMR (500 MHz, CDCl3): 0.09, 0.11 (2 ꢁ s, 6H, –SiMe2);
0.88 (s, 9H, –SitBu); 1.34, 1.49 (2 ꢁ s, 6H, 2 ꢁ –CH3); 2.63 (t, 1H, J
5.4 Hz, –OH); 3.14 (d, 1H, J 5.4 Hz, –OH); 4.07–4.10 (m, 1H, H-4);
4.23–4.27 (m, 1H, H-7); 4.32–4.36 (m, 1H, H-70); 4.57 (d, 1H, J2,3
0
6.1 Hz, H-3); 4.72–4.74 (m, 2H, H-5, H-6); 4.90 (dd, 1H, J6,7 4.1 Hz,
H-2); 5.33 (s, 1H, H-1); 13C NMR (62.8 MHz, CDCl3): ꢂ5.6, ꢂ4.6 (–
SiMe2); 17.7 (–SiC(CH3)3); 24.3, 25.6 (–C(–CH3)2); 25.3 (–SiC(CH3)3);
59.8 (–CH2–); 78.7, 79.5, 86.4, 88.3 (4 ꢁ –CH–); 101.3 (C-1); 112.8 (–
C(–CH3)2); LRMS (m/z, %): 378 (M+ ꢂ15, 0.3); 318 (0.7); 260 (2); 187
The new iminoheptitols 9 and 13 were assayed for their inhib-
itory activity toward commercially available glycosidases.24 Com-
(6); 129 (27); 58 (100); IR (m
, cmꢂ1): 3427 (–OH); 1556, 1378 (–NO2);
pounds
following glycosidases at a concentration of 143
zymes optimal pH: -glucosidase from Saccharomyces cerevisiae,
-glucosidase from Bacillus sterothermophilus, b- -glucosidase
from Almond (Prunus sp.), -galactosidase from green coffee
bean (Coffea sp.), b- -galactosidase from bovine liver, -mannos-
idase from jack bean (Canavalia ensiformis), b- -mannosidase from
Cellullomonas fimi, and b- -galactosidase from bovine liver. Com-
pound 13 was also tested on bovine epididymis -fucosidase
9
and 13 showed no significant activity with the
EA: Calcd for C16H31NO8Si: C, 48.84; H, 7.94; N, 3.56. Found: C, 49.21;
l
g/mL at the en-
H, 8.04; N, 3.30. Data for 6. Mp: 116–123 °C; ½a D23
¼ þ3:2 (c 1.0, chlo-
ꢀ
a-D
roform); 1H NMR (500 MHz, CDCl3): 0.09, 0.11 (2 ꢁ s, 6H, –SiMe2);
0.88 (s, 9H, –SitBu); 1.34, 1.49 (2 ꢁ s, 6H, 2 ꢁ –CH3); 2.60 (t, 1H, J
6.4 Hz, –OH); 3.10 (d, 1H, J 6.1 Hz, –OH); 4.08–4.10 (m, 1H, H-3);
4.23–4.27 (m, 1H, H-5); 4.32–4.37 (m, 1H, H-4); 4.57 (d, 1H, J6,7
a-
D
D
a-D
D
a-D
D
5.8 Hz, H-7); 4.72–4.74 (m, 2H, H-2, H-70); 4.90 (dd, 1H, J6,7 4.0 Hz,
0
D
H-6); 5.33 (s, 1H, H-1); 13C NMR (62.8 MHz, Cl3CD): ꢂ5.7, ꢂ4.7
(2 ꢁ –CH3, –SiMe2); 17.6 (–SiC(CH3)3); 24.4, 25.7 (–C(CH3)2, –
SiC(CH3)3); 59.7 (–CH2–, C-7); 69.2, 78.7, 79.4 (3 ꢁ –CH–); 86.4,
88.4 (2 ꢁ –CH–); 101.3 (–CH–, C-1); 112.7 (s, –C–); LRMS (m/z, %):
378 (M+ – 15, 0.3); 318 (0.7); 260 (2); 187 (6); 129 (27); 58 (100);
a-L
and gave weak but selective inhibition with an IC50 of 1.7 mM.
3. Conclusion
IR (
m
, cmꢂ1): 3427 (–OH); 1556, 1378 (–NO2).
In conclusion, we have reported herein the preliminary results on
anovel strategyforthepreparationofiminosugarsfromnitrosugars.
Specifically, this article concerns the preparation of the novel poly-
hydroxylated azepanes9 and13. The evaluationof these compounds
as glycosidase inhibitors allowed us to establish that the latter com-
4.2. 6-Benzyloxycarbonylamino-1-O-tert-butyldimethylsilyl-6-
deoxy-2,3-di-O-isopropylidene-D-glycero-a-D-manno-heptofura-
nose 6b
pound has a weak but selective inhibition against a-L-fucosidase.
Work is now in progress and is aimed at extending this method-
ology to the pool of tetroses, pentoses, and hexoses, in order to gain
access to a wide range of novel five-, six-, and seven-membered
imino sugars for pharmacological purposes.
Raney nickel (6.7 mL, 10% w/w) was added to a degassed solu-
tion of 1-O-tert-butyldimethylsilyl-6-deoxy-2,3-di-O-isopropyli-
dene-6-nitro-
D
-glycero-
a
-D
-manno-heptofuranose
4
(0.41 g,
1.03 mmol) in methanol (15 mL) and the resulting mixture was

24
A. M. Estévez et al. / Tetrahedron: Asymmetry 21 (2010) 21–26
stirred under a hydrogen atmosphere at room temperature for 2 h.
The suspension was then filtered through a Celite pad and the fil-
trate was evaporated in vacuo to afford 6-amino-1-O-tert-butyldi-
for 4 h. The suspension was filtered through a Celite pad and the
filtrate was evaporated in vacuo to afford a residue, which was
purified by flash column chromatography (chloroform/methanol
85:15) to obtain (2R,3S,4R,5R,6R)-hexahydro-6-(hydroxymethyl)-
methylsilyl-6-deoxy-2,3-di-O-isopropylidene-D-glycero-a-D-man-
no-heptofuranose 6a, which was used for the next step without
further purification. To a solution of this amine in ethyl acetate
(8 mL) was added a saturated aqueous solution of sodium hydro-
gen carbonate (5.5 mL) and the mixture was cooled to 0 °C. Benzyl
chloroformate (1.13 mmol) was added dropwise and the resulting
mixture was stirred at rt for 3 h. The layers were separated and the
aqueous layer was extracted with ethyl acetate (3 ꢁ 20 mL). The
combined organic layers were dried (sodium sulfate), filtered,
and evaporated in vacuo to give a residue, which was purified by
flash column chromatography (ethyl acetate/hexane 1:2) to afford
6-benzyloxycarbonylamino-1-O-tert-butyldimethylsilyl-6-deoxy-
2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]azepine-7,8-diol
8
(0.05 g,
97%) as a clear oil. ½a D23
ꢀ
¼ þ6:3 (c 0.9, methanol); 1H NMR
(300 MHz, MeOD): 1.35, 1.48 (2 ꢁ s, 6H, 2 ꢁ –CH3); 2.93–3.19 (m,
2H, H-8, H-80); 3.67–3.73 (m, 3H, H-6, –CH2OH); 4.01 (d, 1H, J
5.2 Hz, H-3a); 4.18–4.29 (m, 3H, H-8a, H-4, H-5); 13C NMR
(62.8 MHz, MeOD): 24.4, 26.9 (–C(–CH3)2); 46.4 (C-4); 60.9 (C-6);
62.3 (–CH2OH) 70.1, 75.7, 76.5, 77.6 (C-3a, C-7, C-8, C-8a); 109.9
(–C(–CH3)2); LRMS (ESI+, m/z, %): 384 [(M+H)+, 100]; HRMS
(ESI+): Calcd for C10H20NO5 [(M+H)+]: 234.1341. Found: 234.1336.
4.5. (2R,3R,4R,5R,6R)-2-(Hydroxymethyl)azepane-3,4,5,6-
2,3-di-O-isopropylidene-
D
-glycero-
a
-
D
-manno-heptofuranose 6b
tetraol 9
(0.37 g, 72%) as a white foam. ½a D23
ꢀ
¼ þ14:5 (c 0.23, chloroform);
1H NMR (300 MHz, CDCl3): 0.00, 0.03 (2 ꢁ s, 6H, –SiMe2); 0.80 (s,
9H, –SitBu); 1.26, 1.40 (2 ꢁ s, 6H, 2 ꢁ –CH3); 2.29 (br s, 1H, –OH);
2.87 (br s, 1H, –OH); 3.66–4.06 (m, 5H, H-7, H-70, H-6, H-5, H-4);
4.46 (d, 1H, J2,3 5.7 Hz, H-2); 4.88–4.89 (m, 1H, H-3); 5.02–5.03
(m, 2H, –CH2Ph); 5.27 (s, 1H, H-1); 5.63 (d, 1H, J 7.6 Hz, –NH–);
7.23–7.28 (m, 5H, H-Ph); 13C NMR (62.8 MHz, CDCl3): ꢂ5.0, ꢂ4.1
(–SiMe2); 18.2 (–SiC(CH3)3); 25.0, 26.3 (–C(–CH3)2); 26.0 (–
SiC(CH3)3); 54.5 (–CH–); 62.6, 67.3 (2 ꢁ –CH2–); 72.3, 79.3, 80.8,
87.0 (4 ꢁ –CH–); 101.9 (C-1); 112.9 (–C(–CH3)2); 128.5, 129.0
(5 ꢁ –CHPh); 136.7 (–CPh); 157.2 (–C@O); LRMS (IQ+, m/z, %):
A solution of azepine 8 (30 mg, 0.13 mmol) in a 1:1 mixture of
trifluoroacetic acid/water (3.3 mL) was stirred at rt for 17 h. The
solvents were evaporated and the residue was coevaporated with
toluene, to afford (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-
3,4,5,6-tetraol 9 (25 mg, quantitative) as a clear oil. ½a D23
¼ ꢂ3:6
ꢀ
(c 3.2, methanol/water 1:1); 1H NMR (300 MHz, MeOD): 3.09 (dd,
1H, J7,7 13.4 Hz, J7,6 3.0 Hz, H-7); 3.22–3.32 (m, 2H, H-70, H-2);
0
3.70 (dd, 1H, J 11.7 Hz, J 7.0 Hz, –CHOH); 3.83 (dd, 1H, J 11.7 Hz,
J 3.8 Hz, –CHOH); 3.89–3.98 (m, 2H); 4.06–4.12 (m, 2H); 13C
NMR (62.8 MHz, MeOD): 45.3 (C-7); 59.9 (–CH2OH); 60.1 (C-2);
66.3, 67.4, 72.4, 74.2 (C-3, C-4, C-5, C-6); LRMS (ESI+, m/z, %):
194 [(M+H)+, 100]; HRMS (ESI+): Calcd for C7H16NO5 [(M+H)+]:
194.1028. Found: 194.1020.
498 [(M+H)+, 35]; 366 (100); IR ( , cmꢂ1): 3432 (–OH); 1722 (–
m
C@O); EA: Calcd for C24H39NO8Si: C, 57.92; H, 7.90; N, 2.81. Found:
C, 58.27; H, 8.06; N, 2.74.
4.3. 6-Benzyloxycarbonylamino-6-deoxy-2,3-di-O-isopropylidene-
4.6. 6-Benzyloxycarbonylamino-1-O-tert-butyldimethylsilyl-6-
D
-glycero-
a
-
D
-mano-heptofuranose 7
deoxy-2,3-di-O-isopropylidene-L-glycero-a-D-manno-
heptofuranose 10b
To a solution of 6-benzyloxycarbonylamino-1-O-tert-butyldi-
methylsilyl-6-deoxy-2,3-di-O-isopropylidene- -glycero- -man-
D
a-
D
1-O-tert-Butyldimethylsilyl-6-deoxy-2,3-di-O-isopropylidene-6-
nitro- -glycero- -manno-heptofuranose 5 (0.83 g, 2.10 mmol) was
hydrogenated and protected following the same procedure used
no-heptofuranose 6b (0.33 g, 0.67 mmol) in THF (6 mL) was added
tetrabutylammonium fluoride (0.77 mL, 1 M solution in THF). The
mixture was stirred at rt for 16 h, after which the solvent was
evaporated, and the residue was taken up in ethyl acetate
(10 mL) and washed with water (3 ꢁ 5 mL). The organic layer
was dried (sodium sulfate), filtered, and evaporated in vacuo. Puri-
fication of the resulting residue by flash column chromatography
(methanol/dichloromethane 10:1) yielded 6-benzyloxycarbonyl-
L
a-D
for 4, to afford 6-benzyloxycarbonylamino-1-O-tert-butyldimethyl-
silyl-6-deoxy-2,3-di-O-isopropylidene-
L
-glycero-
a
-
D
-manno-heptof-
uranose 10b (0.89 g, 85%) as a white foam. ½a D23
ꢀ
¼ þ18:1 (c 0.35,
chloroform); 1H NMR (300 MHz, CDCl3): ꢂ0.04, 0.02 (2 ꢁ s, 6H, –
SiMe2); 0.77 (s, 9H, –SitBu); 1.23, 1.39 (2 ꢁ s, 6H, 2 ꢁ –CH3); 3.19
(br s, 1H, –OH); 3.62–4.16 (m, 5H, H-7, H-70, H-6, H-5, H-4); 4.45 (d,
1H, J2,3 6.0 Hz, H-2); 4.72–4.76 (m, 1H, H-3); 4.99 (s, 2H, –CH2Ph);
5.22 (s, 1H, H-1); 5.58 (d, 1H, J 8.5 Hz, –NH–); 7.24–7.28 (m, 5H, H-
Ph); 13C NMR (62.8 MHz, CDCl3): ꢂ5.7, ꢂ4.7 (–SiMe2); 17.6 (–
SiC(CH3)3); 24.5, 25.8 (–C(–CH3)2); 25.4 (–SiC(CH3)3); 52.8 (–CH–);
64.1, 66.7 (2 ꢁ –CH2–); 69.8, 78.2, 79.9, 86.6 (4 ꢁ –CH–); 101.2 (C-
1); 112.3 (–C(–CH3)2); 128.1, 128.4 (5 ꢁ –CHPh); 136.2 (–CPh);
156.5 (–C@O); LRMS (CI+, m/z, %): 498 [(M+H)+, 20]; 366 (100); IR
amino-6-deoxy-2,3-di-O-isopropylidene-D-glycero-a- -manno-
heptofuranose 7 (0.26 g, quantitative) as a clear oil. ½aDꢀD23 ¼ þ3:7 (c
1.0, methanol); 1H NMR (300 MHz, MeOD): 1.23 1.37 (2 ꢁ s, 6H,
2 ꢁ –CH3); 3.86–4.13 (m, 5H); 4.50 (d, 1H, J2,3 5.5 Hz, H-2); 4.84
(br s, 1H); 5.00 (s, 2H, –CH2Ph); 5.33 (s, 1H, H-1); 6.14 (d, 1H, J
7.8 Hz, –NH–); 7.26–7.28 (m, 5H, H-Ph); 13C NMR (62.8 MHz,
CDCl3): 26.0, 26.3 (–C(–CH3)2); 54.6 (–CH–); 61.9, 67.4 (2 ꢁ –
CH2–); 71.3, 78.1, 80.7, 85.7 (4 ꢁ –CH–); 101.3 (C-1); 113.0 (–C(–
CH3)2); 128.4, 128.9 (5 ꢁ –CHPh); 136.6 (–CPh); 157.5 (–C@O);
(m
, cmꢂ1): 3437 (–OH); 1707 (–C@O); EA: Calcd for C24H39NO8Si: C,
57.92; H, 7.90; N, 2.81. Found: C, 57.98; H, 8.24; N, 2.67.
LRMS (IQ+, m/z, %): 384 [(M+H)+, 45]; 366 (100); IR ( , cmꢂ1):
m
3395 (–OH); 1699 (–C@O); EA: Calcd for C18H25NO8: C, 56.39; H,
4.7. 6-Benzyloxycarbonylamino-6-deoxy-2,3-di-O-
6.57; N, 3.65. Found: C, 55.99; H, 7.01; N, 3.44.
isopropylidene-L-glycero-a-D-manno-heptofuranose 11
4.4. (3aR,6R,7R,8R,8aS)-Hexahydro-6-(hydroxymethyl)-2,2-dime-
thyl-3aH-[1,3]dioxolo[4,5-c]azepine-7,8-diol 8
6-Benzyloxycarbonylamino-1-O-tert-butyldimethylsilyl-6-deoxy-
2,3-di-O-isopropylidene- -glycero- -manno-heptofuranose 10b
L
a-D
(0.19 g, 0.40 mmol) was desilylated following the same procedure
Palladium black (0.02 g, 20% w/w) and ammonium formate
(0.15 g, 2.30 mmol) were added to a degassed solution of 6-benzyl-
used for 7b, yielding 6-benzyloxycarbonylamino-6-deoxy-2,3-di-
O-isopropylidene-L-glycero-a-D-manno-heptofuranose 11 (0.14 g,
oxycarbonylamino-6-deoxy-2,3-di-O-isopropylidene-
D-glycero-a-
94%) as a clear oil. ½a D23
ꢀ
¼ ꢂ0:1 (c 0.9, methanol); 1H NMR
D-mano-heptofuranose 7 (0.09 g, 0.23 mmol) in methanol (7 mL)
(300 MHz, MeOD): 1.24 1.36 (2 ꢁ s, 6H, 2 ꢁ –CH3); 3.55–3.59 (m,
2H); 4.02–4.08 (m, 3H); 4.47 (d, 1H, J2,3 5.8 Hz, H-2); 5.01 (s, 2H,
–CH2Ph); 5.16 (s, 1H, H-1); 7.23–7.25 (m, 5H, H-Ph); 13C NMR
and acetic acid (two drops). The resulting mixture was stirred un-
der a nitrogen atmosphere at rt for 12 h and then heated at 50 °C

A. M. Estévez et al. / Tetrahedron: Asymmetry 21 (2010) 21–26
25
(62.8 MHz, MeOD): 25.5, 26.9 (–C(–CH3)2); 55.6 (–CH–); 63.2, 68.0
(2 ꢁ –CH2–); 68.6, 80.4, 81.9, 102.7 (4 ꢁ –CH–); 102.7 (C-1); 113.8
(–C(–CH3)2); 129.4, 129.9 (5 ꢁ –CHPh); 138.7 (–CPh); 159.3 (–
84.6, 89.7 (5 ꢁ –CH–); 105.4 (C-1); 113.0 (–C(–CH3)2), 128.0,
128.1, 128.3, 128.6 (5 ꢁ –CH–), 136.8 (–C@O).
C@O); LRMS (IQ+, m/z, %): 384 [(M+H)+, 11]; 366 (100); IR (
cmꢂ1): 3395 (–OH); 1699 (–C@O).
m,
4.11. (3aR,6R,7R,8R,8aS)-Hexahydro-6-(hydroxymethyl)-2,2-
dimethyl-3aH-[1,3]dioxolo[4,5-c]azepine-7,8-diol 8
4.8. (3aR,6S,7R,8R,8aS)-Hexahydro-6-(hydroxymethyl)-2,2-
dimethyl-3aH-[1,3]dioxolo[4,5-c]azepine-7,8-diol 12
Palladium black (0.02 g, 20% w/w) and ammonium formate
(0.15 g, 2.30 mmol) were added to a degassed solution of 1-O-ben-
zyl-6-deoxy-2,3-di-O-isopropylidene-6-nitro-D-glycero-a-D-man-
6-Benzyloxycarbonylamino-6-deoxy-2,3-di-O-isopropylidene-
L
-
no-heptofuranose 15 (0.09 g, 0.23 mmol) in methanol (7 mL) and
acetic acid (two drops) and the resulting mixture was heated at
50 °C for 16 h. The suspension was filtered through a Celite pad
and the filtrate was evaporated in vacuo to afford a residue,
which was purified by flash column chromatography (chloro-
form/methanol 85:15) to obtain (2R,3S,4R,5R,6R)-hexahydro-6-
(hydroxymethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]azepine-
7,8-diol 8 (0.05 g, 97%) as a clear oil.
glycero- -manno-heptofuranose 11 (0.10 g, 0.25 mmol) was
a-D
hydrogenated following the same procedure used for 7, to obtain
(2R,3S,4R,5R,6S)-hexahydro-6-(hydroxymethyl)-2,2-dimethyl-3aH-
[1,3]dioxolo[4,5-c]azepine-7,8-diol 12 (55 mg, 95%) as a clear oil.
½
a 2D3
ꢀ
¼ ꢂ1:7 (c 0.12, methanol); 1H NMR (300 MHz, MeOD): 1.26,
1.39 (2 ꢁ s, 6H, 2 ꢁ –CH3); 2.93–3.00 (m, 1H, H-80); 3.11–3.22 (m,
2H, H-8, H-6); 3.70–3.78 (m, 3H); 4.07 (d, 1H, J 4.0 Hz, H-3a);
4.18–4.29 (m, 3H); 13C NMR (62.8 MHz, MeOD): 23.9, 26.4 (–C
(–CH3)2); 47.4 (C-4); 61.9 (C-6); 62.3 (–CH2OH) 72.4, 73.7, 75.6,
80.7 (C-3a, C-7, C-8, C-8a); 109.6 (–C(–CH3)2); LRMS (ESI+, m/z,
%): 384 [(M+H)+, 100]; HRMS (ESI+): Calcd for C10H20NO5
[(M+H)+]: 234.1341. Found: 234.1336.
4.12. (3aR,6S,7R,8R,8aS)-Hexahydro-6-(hydroxymethyl)-2,2-
dimethyl-3aH-[1,3]dioxolo[4,5-c]azepine-7,8-diol 12
1-O-Benzyl-6-deoxy-2,3-di-O-isopropylidene-6-nitro-
L-glycero-
a-D-manno-heptofuranose 16(0.10 g, 0.25 mmol)washydrogenated
4.9. (2S,3R,4R,5R,6R)-2-(Hydroxymethyl)azepane-3,4,5,6-tetraol
13
following the same procedure used for 15, to obtain (2R,3S,4R,5R,6S)-
hexahydro-6-(hydroxymethyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-
c]azepine-7,8-diol 12 (55 mg, 95%) as a clear oil.
Azepine 12 (47 mg, 0.20 mmol) was deprotected following the
same procedure used for 8, to afford (2S,3R,4R,5R,6R)-2-(hydroxy-
methyl)azepane-3,4,5,6-tetraol 13 (38 mg, 98%) as a clear oil.
4.13. Biological assays21
½
a 2D3
ꢀ
¼ ꢂ59:0 (c 0.9, in methanol/water 1:1); 1H NMR (300 MHz,
All enzymes and para-nitrophenyl substrates were purchased
from Sigma, with the exception of b-mannosidase, which was ob-
tained from Megazyme. Enzymes were assayed at 27 °C in 0.1 M
citric acid/0.2 M disodium hydrogen phosphate buffers at the opti-
mum pH for the enzyme. The incubation mixture consisted of
0
MeOD): 3.00 (dd, 1H, J7,7 13.3 Hz, J7,6 3.0 Hz, H-7); 3.17–3.25 (m,
2H, H-70, H-2); 3.62 (dd, 1H, J 12.1 Hz, J 7.2 Hz, –CHOH); 3.74
(dd, 1H, J 12.1 Hz, J 4.0 Hz, –CHOH); 3.80–3.88 (m, 2H); 3.97–
4.05 (m, 2H); 13C NMR (62.8 MHz, MeOD): 46.4 (C-7); 61.0
(–CH2OH); 61.2 (C-2); 67.5, 68.5, 73.6, 75.4 (C-3, C-4, C-5, C-6);
LRMS (ESI+, m/z, %): 194 [(M+H)+, 100]; HRMS (ESI+): Calcd for
C7H16NO5 [(M+H)+]: 194.1028. Found: 194.1023.
10
inhibitor, and 50
substrate made up in buffer at the optimum pH for the enzyme.
The reactions were stopped by the addition of 70 L 0.4 M glycine
l
L enzyme solution, 10
lL of 1 mg/mL aqueous solution of
l
L of the appropriate 5 mM para-nitrophenyl
l
4.10. 1-O-Benzyl-6-deoxy-2,3-di-O-isopropylidene-6-nitro-
D
-
(pH 10.4) during the exponential phase of the reaction, which had
been determined at the beginning using uninhibited assays in
which water replaced inhibitor. Final absorbances were read at
405 nm using a Versamax microplate reader (Molecular Devices).
Assays were carried out in triplicate, and the values given are
means of the three replicates per assay.
glycero- -manno-heptofuranose 15 and 1-O-benzyl-6-deoxy-
a
-D
2,3-di-O-isopropylidene-6-nitro-L-glycero-a-D-manno-
heptofuranose 16
To a solution of 1-O-benzyl-2,3-O-isopropylidene-a-D-lyxo-pen-
todialdo-1,4-furanose 14 (1.22 g, 4.27 mmol) in dry methanol
(30 mL) were added nitroethanol (0.9 mL, 12.91 mmol) and so-
dium methoxide (0.66 g, 12.32 mmol) and the resulting mixture
was stirred at rt for 14 h. The reaction was neutralized with DOW-
EX 50 W resin, filtered, and the filtrate was evaporated to dryness
under reduced pressure. The residue was partitioned between
water and dichloromethane and the organic layer was dried (mag-
nesium sulfate), filtered, and evaporated in vacuo. The residue was
purified by flash column chromatography (ethyl acetate/hexane
1:2) to afford 1-O-benzyl-6-deoxy-2,3-di-O-isopropylidene-6-ni-
Acknowledgments
We thank the Spanish Ministry of Science and Innovation for
financial support (CTQ2005–00555/BQU and CTQ2008–03105/
BQU) and for F.P.U. grants to José M.O. and A.M.E., and the Xunta
de Galicia for an Isidro Parga Pondal grant to Raquel G. Soengas.
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D
-glycero-
a
-
D
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