An easy route to seven-membered iminocyclitols from aldohexopyranosyl enamines

Article abstract of DOI:10.1016/S0957-4166(02)00377-4

A new stereocontrolled and high yielding synthesis of biologically active polyhydroxyperhydroazepines is reported starting from easily available glycosylenamines (D-gluco, D-manno, and D-galacto configurations), which are transformed into 1,6-azaanhydropy

Full text of DOI:10.1016/S0957-4166(02)00377-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1743–1753
An easy route to seven-membered iminocyclitols from
aldohexopyranosyl enamines
a,
a
b
a
b
´
Jose´ Fuentes, * Consolacio´n Gasch, David Olano, M. Angeles Pradera, Guillermo Repetto and
Francisco J. Sayagoa
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
bInstituto Nacional de Toxicolog´ıa de Sevilla, Apartado 863, E-41080 Sevilla, Spain
Received 25 June 2002; accepted 12 July 2002
Abstract—A new stereocontrolled and high yielding synthesis of biologically active polyhydroxyperhydroazepines is reported
starting from easily available glycosylenamines (D-gluco, D-manno, and D-galacto configurations), which are transformed into
1,6-azaanhydropyranose derivatives. O- and N-Deprotection of the latter, followed by reduction with sodium cyanoborohydride,
gives the target chiral iminocyclitols. The method is based on the capacity of the dialkoxycarbonylvinyl group to stabilize an
amide ion, and the only limitation is the necessity for the starting glycosylenamine to have b-D-configuration. The inhibitory
activity of several intermediate iminocyclitols and aldopyranosylenamines on different a- and b-glycosidases is also reported.
© 2002 Published by Elsevier Science Ltd.
1. Introduction
We have recently communicated12 our previous results
on a new method for the preparation of polyhydroxy-
perhydroazepines starting from N-diethoxycarbonyl-
vinyl glycosylamines. Herein, we describe the prepara-
tion of glycosylenamines 1–16 having in many cases
(4–6, 9, 10, 13, and 16) an OMs substituent on C-6,
which is suitable for the formation of the 1,6-anhy-
droazasugars 17–26. The O-debenzoylation of 18, 22,
and 25, followed by N-deprotection, leads to 27–29,
which by cleavage of the C1ꢀO bond under reductive
conditions, produces the chiral polyhydroxyperhy-
droazepines (azasugar analogues) 30–32 as their ammo-
nium salts. From these, the known5a free iminocyclitols
33–35 were prepared. The method to form the C6ꢀN
bond is a valuable alternative to the SN2 displacement
of a sulphonyloxy or cyclic sulphate group with sodium
azide, because, in our case, the seven-membered ring is
formed directly, shortening the synthetic route.
The iminocyclitols are sugar analogues containing an
imino group instead of an oxygen atom in the ring.
These compounds have been discovered as natural
products, and present important pharmaceutical activi-
ties due to their glycosidase- and glycosyltransferase-
inhibitory properties.1 Much effort has been devoted
toward syntheses of five-2 and six-3 membered iminocy-
clitol families, as they are able to mimic the transition
state of enzymatic reactions.4 However, little attention
has been directed to the synthesis of seven-membered
iminocyclitols
(the
polyhydroxyperhydroazepines)
despite data in the literature5 indicating that many of
these compounds have higher glycosidase-inhibition
potencies than their five- and six-membered counter-
parts. This may be due to the flexibility of the perhy-
droazepine ring system, permitting the ring to adopt
quasi-flattened conformations, which could lead to
more favourable binding within the active site of the
enzyme.3a,5,6 Only a few chemical and chemoenzymatic
methods for the syntheses of polyhydroxyperhy-
droazepines have been reported,2g,3a,7 although interest
has been growing over the last 3 years,6,8–10 also includ-
ing the preparation of related heterocycles having an
additional nitrogen or sulphur atom.11
2. Results and discussion
The synthetic route for the preparation of the seven-
membered iminocyclitols is outlined in Scheme 1. The
key step in the synthesis is the formation of a 1,6-anhy-
dro derivative; consequently the corresponding sub-
stituents should have
a cis-relationship, that is
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00377-4

1744
J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
Scheme 1. Reagents and conditions: (i) MeONa/DMF, rt, 20 mmHg, 15 min; (ii) MeONa/MeOH, rt, 4 h; (iii) Cl2/CH2Cl2, rt, 15
+
min; (iv) NaCNBH3/AcOH, rt, 24 h; (v) Dowex-50W.NH4 form. 1×20 cm.
monosaccharide enamines with b-D-configuration are
the most suitable and available starting materials.
Additionally, the configuration of C2, C3, C4 and C5 in
the sugar moiety is retained in the final iminocyclitols.
Thus, the b-D-aldopyranosylenamines 1–3 with D-
gluco, D-galacto, and D-manno configurations13 were
chosen as starting materials. The partially O-acylated
b-D-glucosylenamines 7 and 8, prepared14 from 1, have
also been used. With the aim of forming products
useful for enzymatic studies and, simultaneously, for
further transformation, the 6-O-mesyl derivatives 4–6,
9, 10, 13, and 16 were prepared (Scheme 1) from the
corresponding N-diethoxycarbonylvinyl-b-D-glycopy-
ranosyl amines by per-O-mesylation with mesyl chlo-
ride (“4–6), 6-O-mesylation (“9, 10) or through
conventional strategies of one-pot 6-O-tritylation and
benzoylation (“11, 14), de-O-tritylation (“12, 15),
and O-mesylation (“13, 16). The presence of the trityl
Treatment of the 6-O-mesylated N-diethoxycar-
bonylvinyl-D-glucopyranosyl amines 4–6, 9, 10, 13, and
16 with one equiv. of sodium methoxide in DMF, in a
similar way to that we have described16 for 4-O-mesyl
derivatives, gave the 1,6-anhydroazapyranoses 17, 18,
1
20–22, 24, and 25 in high yields. The H NMR spectra
of these compounds (Table 1) contained no NH proton
signals and showed a singlet for the HCꢁ of the enam-
ino moiety (ꢁCHNR2) instead of the doublet
(ꢁCHNHR) of the spectra of the parent compounds.
The signals for H1 were shifted downfield (:0.8 ppm),
whereas the resonances for H6a and H6b were shifted
upfield as corresponds to the substitution of the sulpho-
nyloxy group by an enamino group. These changes are
analogous, but quantitatively smaller (except in the case
of l C6), to those described for 1,4-anhydroaza com-
pounds,16 where a five-membered ring is formed and a
1,4B conformation of the sugar ring is a requirement.
Other differences observed in the NMR spectra were
shielding in the chemical shifts for HCꢁ, very marked
changes in all coupling constants of the sugar ring
(which were in accord with a conformational change
due to the formation of the bicyclic system, see below),
small shifts in the chemical shift of C1, a strong (18–20
ppm) upfield shift in the resonance of C6, and signifi-
cant changes in the chemical shifts for the resonances of
the carbons of the enamino moiety.
group in 11 and 14 was evident from NMR (1H and 13
C
signals for the phenyl rings, the resonances of H6a and
H6b at 3.25–3.50 ppm and the resonance of C6 at :61
ppm, see Table 1) and MS analyses (peak for Ph3C+ at
m/e 243).14,15 The NMR data of the 6-hydroxy deriva-
tives 12 and 15 were very close to those for 11 and 14,
except for a downfield shift of :0.4 ppm in the signals
for H6a and H6b.15 The chemical shifts for the reso-
nances of H6a, H6b and C6 for the 6-O-mesyl deriva-
tives 4–6, 9, 10, 13, and 16 also showed strong
deshielding (:0.6 and :6 ppm, respectively) compared
to the values for the corresponding hydroxy derivatives,
as corresponds to the formation of the sulphonyloxy
compound.
The formation of 17, 18, 20–22, 24, and 25 can be
explained by the presence of an intermediate amide
ion (stabilized by the dialkoxycarbonylvinyl group2e),

J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
Table 1. Relevant NMR data (l, ppm; J, Hz) for compounds 4–6 and 9–26
Sugar ring
lH-6b
1745
Enamino moiety
J1,NH l=CH l=CH
lH-1
J1,2
lH-6a
J6a,6b J5,6a
J5,6b lC-1
lC-6
lNH
l=C
4
5
6
9
4.70t
4.74t
5.03dd
4.87t
9.2
9.0
0.8
9.8
8.9
8.7
8.9
8.9
1.1
1.1
1.1
1.4
0.0
4.64dd
4.37m
4.61dd
4.46–4.42m
3.76m
3.47dd
3.84dd
’4.42–4.32m“
3.54dd
4.45dd
4.32m
4.40dd
4.33–4.15m
3.61m
11.6
2.1
4.3
86.5
86.8
84.0
87.3
87.0
87.1
87.8
87.9
84.4
85.0
84.8
88.6
89.4
93.2
89.0
87.9
89.3
92.6
89.5
89.5
93.7
66.6
65.9
67.0
66.8
66.0
60.5
60.4
66.0
61.8
61.3
67.5
48.4
48.1
49.0
47.7
47.5
47.3
48.5
47.1
47.6
48.5
9.32dd
9.39dd
9.49dd
9.40dd
9.20dd
9.39dd
9.50dd
9.51dd
9.2
9.0
9.2
9.8
8.9
8.7
8.9
8.9
8.0
8.9
8.8
–
–
–
–
–
–
–
–
–
7.96d
7.98d
8.01d
7.98d
7.93d
7.99d
8.02d
8.01d
8.24d
8.11d
8.10d
7.59s
7.84s
7.74s
7.62s
7.56s
7.84s
7.72s
7.64s
7.84s
7.80s
156.8
157.1
156.7
156.9
157.2
157.4
157.5
157.2
156.6
156.7
156.6
144.9
144.6
147.5
144.0
145.0
144.7
147.6
144.4
144.8
148.1
96.1
95.9
95.2
95.5
94.8
94.6
94.6
95.2
93.9
94.5
94.9
98.7
97.8
95.8
97.7
98.5
97.6
95.3
98.2
97.0
95.0
a
a
a
11.7
2.2
5.0
a
a
a
a
a
a
10 4.57t
11 4.75t
12 4.85t
13 4.86t
14 5.11dd
15 4.13dd
16 4.16dd
17 5.55bs
18 5.65s
19 5.32bs
20 5.38bs
21 5.49bs
22 5.59s
23 5.24bs
24 5.43bs
25 5.50bs
26 5.13bs
3.26t
3.65dd
9.0
5.4
9.0
11.9
6.6
6.7
a
a
a
3.26dd
10.7
2.2
3.5
9.56dd
9.48dd
9.51dd
a
a
a
’3.92–3.78m“
’4.48–4.47m“
3.71d
a
a
a
a
a
3.48d
10.7
–
–
–
–
–
–
–
–
–
–
3.82d
3.54m
3.61d
3.89d
3.00d
3.70m
3.74d
3.87d
3.62d
3.70dd
3.40m
3.40dd
3.41m
3.63dd
3.33m
3.36dd
3.82dd
3.26dd
10.9
–
6.4
a
a
a
1.4
a
10.7
10.5
–
–
6.7
a
1.3
–
10.5
–
6.4
a
a
a
a
0.9
11.1
10.9
10.5
–
–
–
6.5
6.5
7.1
a
a
–
a Not measured.
which is formed by attack of methoxide ion on the NH
group (Scheme 2). Intramolecular nucleophilic displace-
ment of the 6-OMs group gives the 1,6-anhydro-azasugar
derivative. Stereochemically, this reaction is limited to
sugar derivatives with b-D configuration. Debenzoyla-
tion of 18, 22, and 25 with sodium methoxide afforded
19, 23, and 26, respectively, in high yields, the 1H NMR
spectra of which showed the expected upfield shifts in the
signals for H2, H3, and H4 (see Section 4).
The bibliographic data on conformational analysis
1
of 1,6-anhydrosugars16 indicate that the C4(D) form is
the major conformation, although the B3,0 conformation
has also been postulated. Both conformations present
1,3-diaxial interactions and/or eclipsing of electron
pairs. The only precedent17 for 1,6-anhydro-azasugars
refers to N-triphenylphosphonio derivatives, also
proposing the 1C4(D) conformation. The 1H NMR data
of compounds 17–26 were indicative of the 1C4(D)
OEt
-
-
O
δ
MeO-
δ
O
-
δ
N
OMs
O
MsO
RO
O
OEt
OEt
H
N
RO
RO
17, 18, 20, 22, 24, 25
O
CO2Et
En
OR
OR
OR
4-6, 9, 10, 13, 16
Scheme 2.
Figure 1. Preferred conformations of 17–26 in CDCl3 solutions.

1746
J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
conformation distorted in the region C2, C3, C4 (Fig.
1a). The J2,3 value :0 Hz in D-gluco (17–20) and
D-galacto (21–23) compounds indicates a dihedral
angle of 90°; the J3,4 value, also :0 Hz, in D-gluco and
D-manno derivatives (24–26) supports the same angle
between H3 and H4. In the D-manno derivatives the J2,3
values (5.1–5.3 Hz) indicate an angle close to 38°. The
J3,4 values (:5.0 Hz) for the D-galacto compounds also
support the indicated conformation. For compounds
17, 19 (D-gluco), 21 (D-galacto), and 24 (D-manno) an
H1–H3 coupling constant of 0.9–1.0 Hz, indicative of a
W arrangement between the corresponding protons,
was measured, which also ruled out the B3,0
conformation.
boron atom to C1 then takes place (37) with simulta-
neous bonding of the boron atom and the endocyclic
oxygen to give 38. The process is repeated with three
molecules of 27–29. Final hydrolysis produces 30–32.
Attempts to carry out the reduction on the enamino
derivatives 19, 23, and 26 were unsuccessful. Probably,
the enamino nitrogen atom, less basic than the amino
group of 27–29, is not protonated under the reaction
conditions, and as a result attack of hydride ion on C1
is not favoured. Thus, this observation supports the
proposed mechanism.
Treatment of 30–32 with Dowex–50W resin produced
the target polyhydroxyperhydroazepines 33–35, whose
physical data were coincident with the data reported in
the literature.5
In all cases, H6a resonated as a doublet (J6a,6b=11.1,
J5,6a:0 Hz), which permitted the identification of H6a,
and H6b as the endo and exo protons, respectively (Fig.
1b), which also supports the assigned conformation.
Attempts to carry out similar sequences starting from
the tri-O-acetyl derivative 8, and from the per-O-mesyl
compounds 17, 21, and 24 were either low-yielding or
unsuccessful. In the case of 8, acetyl migrations to the
primary hydroxyl group were the main reactions, and
for the per-O-mesyl derivatives (17, 21, and 24) elimina-
tion reactions were predominant.
N-Deprotection of 19, 23, and 26 with chlorine in
chloroform18 gave the corresponding 1,6-anhydro-aza-
sugar derivative 27–29 in virtually quantitative yield.
Compounds 27–29 were characterized by their FABMS
spectra, and used directly in the next step of the
sequence.
The inhibitory potential of several iminocyclitols and
aldohexopyranosyl enamines was determined on vari-
ous glycosidases (a-glucosidase, b-galactosidase and b-
glucosidase). The compounds were selected according
to their hydrosolubilities (1–4, 17, 19, 23 and 26), and
the results are listed in Table 2.
The iminocyclitol ammonium acetates 30–32 were
obtained by reaction of 27–29 with sodium cyanoboro-
hydride in acetic acid. The H7a, H7b19 resonances
appeared at 3.16–3.36 ppm, whereas the signal for the
corresponding proton (H1) in the parent compounds
(19, 23, 26) appeared at 5.13–5.32 ppm. Similar differ-
ences were observed in the resonances of C7 (:47.6
ppm) in 30–32 and C1 (92.6–93.7 ppm) in compounds
19, 23, and 26.
All of the compounds assayed were weak inhibitors or
did not inhibit the glycosidases, even at the millimolar
range. As expected, no activity of 1–4 was found on
a-glucosidase, due to the b-configuration. The poor
inhibition by 17, 19, 23 and 26 on the three enzymes
could be explained if they were forced to adopt a
different conformation to the substrate. For b-galac-
tosidase, the most active inhibitors were 23, 3, 19 and
26, whereas for b-glucosidase, the most active inhibitors
were 17, 2, 4, and 26.
A possible mechanism for the formation of 30–32 is
depicted in Scheme 3. The starting compound is proto-
nated at the nitrogen atom (36), which produces an
increase in the positive character of C1 of the sugar ring
(C7 of the azepine ring). Transfer of hydride from the
OAc
H
δ
H
OAc
OH
H
H
H
N
N
δ
N
δ
δ
H
OBR
O
O
OH
OH
Na
HO
HO
HO
OH
OH
OH
27-29
36
37
R = H3CN
OAc
H
H
H
N
H
Na
R'BO
HO
H2O
OH
OH
38
R' = H2CN
Scheme 3.

J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
1747
Table 2. Comparison of the inhibition on various glycosidases of several iminocyclitols and aldohexopyranosyl enamines
Enzyme
a-Glucosidase baker’s yeast
b-Glucosidase almonds
b-Galactosidase bovine liver
% Inha
Kib
IC50
% Inh
Ki
IC50
% Inh
Ki
IC50
b
Compound
1
2
3
4
17
19
23
26
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
N.I.
28
27
27
N.I.
N.I.
31
25
25
7.7
2.1
6.6
N.I.
N.I.
*
4.4
1.5
3.8
N.I.
N.I.
*
4
8.6
4.8
N.I.
N.I.
N.I.
N.I.
8
N.I.
N.I.
N.I.
N.I.
2.4
N.I.
N.I.
N.I.
N.I.
1.7
4.2
4.1
2.7
2.6
21
5
1.5
3.8
1.2
2.4
a % Inhibition determined at 1 mM concentration of inhibitor; N.I.: no inhibition.
b Values are given in mM.
* No non-competitive inhibitor.
3. Conclusions
layer was washed with 2N H2SO4 and saturated
aqueous NaHCO3, dried over MgSO4, filtered, and
concentrated.
In conclusion, the use of glycosylenamines in a new,
short, experimentally easy and high-yielding synthetic
route to polyhydroxyperhydroazepines is reported. The
dialkoxycarbonylvinyl group is used to protect the
amino function and to stabilize the intermediate amide
ion. The configuration of the final product is defined by
the starting glycosylenamine. The only limitation of the
method is the need for the starting amino sugar to have
the b-D-configuration.
The inhibition tests were performed20 on a-
dase from baker’s yeast, b- -glucosidase from almonds
-galactosidase from bovine liver, which were
D-glucosi-
D
and b-
D
purchased from Sigma Chemical Co.
The inhibition constants (Ki) and the nature of the
inhibition were determined from Lineweaver–Burk
plots. A typical enzymatic assay (final volume 160 mL)
contains 0.01–0.5 units/mL of the enzyme and an
aqueous solution of the appropriate p-nitrophenyl gly-
coside substrates at various final concentrations ranging
from 3.0×10−5 to 6.2×10−3 mM buffered to the opti-
mum pH of the enzyme.
4. Experimental
4.1. General methods
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. A Perkin–Elmer Model
141 MC polarimeter, 1 or 10 cm tubes, and solutions in
CH2Cl2, were used for the measurement of specific
rotations. IR spectra were recorded for KBr discs on a
Bomen Michelson MB-120 FTIR spectrophotometer.
1H (and 13C NMR) spectra were recorded at 500 (125.7)
or 300 (75.5) MHz with, respectively, Bru¨ker 500
AMX, Bru¨ker 300 AMX instruments. Chemical shifts
are given in ppm and tetramethylsilane was the internal
standard. Assignments were confirmed by homonuclear
2D COSY correlated experiments. Heteronuclear 2D
correlated spectra were obtained in order to assist in
carbon resonance assignments. Mass spectra (EI, CI
and FAB) were recorded with a Kratos MS-80RFA or
a Micromass AutoSpecQ instrument with a resolution
of 1000 or 10000 (10% valley definition). For the FAB
spectra, ions were produced by a beam of xenon atoms
(6–7 KeV), using 3-nitrobenzyl alcohol and thioglycerol
as matrix and NaI as salt. TLC was performed on Silica
Gel HF254, with detection by UV light or charring with
H2SO4. Silica Gel 60 (Merck, 70–230 and 230–400
mesh) was used for preparative chromatography. The
term ‘conventional acetylation’ means treatment with
Ac2O–pyridine (1:1 v/v, 10 mL for 1 g of sample)
overnight. The reaction mixture was then poured into
ice-water and extracted with CH2Cl2 and the organic
Enzyme and inhibitor were incubated in a 96-well
polystyrene microplate for 15 min at 37°C and the
reaction was started by addition of the substrate. After
15 min of incubation at 37°C, the reaction was stopped
by addition of 0.1 mL of 0.5 M sodium hydroxide.
The p-nitrophenolate formed was quantified by measur-
ing the absorption at 414 nm on a microplate reader
(Labsystem Multiskan RC). Under the conditions of
the assay, the released p-nitrophenolate led to optical
densities linear with both time of the reaction and
concentration of the substrate.
4.2. Preparation of compounds 4–6, 9, 10, 13, 16
To a cooled (0°C) stirred solution of the corresponding
N - (2,2 - diethoxycarbonylvinyl) - b - D - glycopyranosyl-
amine 1, 2, 3, 7, 8, 12 and 15 (m g) in pyridine (y mL)
under argon, a solution of mesyl chloride (x mL) was
dropped. The mixture was stirred at rt for t min, the
solution was poured into ice-water and extracted with
CH2Cl2, the organic layer was separated, washed with 1
M sulphuric acid, saturated aqueous sodium hydrogen-
carbonate, and water, dried (MgSO4), filtered and evap-
orated to dryness. The residue was purified by column
chromatography.

1748
J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
4.2.1.
N-(2,2-Diethoxycarbonylvinyl)-2,3,4-6-tetra-O-
-glucopyranosylamine, 4. m=1.00 (2.86
Ms), 37.6 (Ms), 14.2, 14.1 (2 CH2CH3). Anal. calcd for
C18H31NO17S4: C, 32.67; H, 4.72; N, 2.12; S, 19.38.
Found: C, 32.92; H, 4.72; N, 2.16; S, 18.93%.
mesyl-b-
D
g
mmol); x=1.56 mL (17.2 mmol); y=40 mL; t=3.0 h.
Column chromatography (EtOAc/hexane, 1:1) gave 4
as an amorphous solid. Yield 98%; [h]2D2 −30 (c 1.0,
CH2Cl2); FABMS m/z 684 [(M+Na)+]; IR 3036, 2945,
4.2.4.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
-glucopyranosylamine, 9. m=2.00 g
vinyl)-6-O-mesyl-b-
D
1707, 1615, 1354, 1244, 1179, 959, 812 cm−1; H NMR
1
(3.02 mmol); x=0.66 mL (7.26 mmol); y=90 mL;
t=24 h. Column chromatography (toluene/methanol,
9:1) gave 9 as a solid. Yield 73%; mp 150–152 (ether);
[h]2D8 −33 (c 1.1, CH2Cl2); FABMS m/z 762 [(M+Na)+];
IR 2980, 1732, 1615, 1454, 1362, 1262, 1177, 1092,
(300 MHz, CDCl3) l 9.32 (dd, 1H, JNH,1=9.2,
J
NH,HCꢁ=12.8, NH), 7.96 (d, 1H, HCꢁ), 5.01 (t, 1H,
J2,3=J3,4=9.2, H-3), 4.87 (t, 1H, J4,5=9.2, H-4), 4.80
(t, 1H, J1,2=9.2, H-2), 4.70 (t, 1H, H-1), 4.64 (dd, 1H,
5,6a=2.1, J6a,6b=11.6, H-6a), 4.45 (dd, 1H, J5,6b=4.3,
1026, 970, 802, 710 cm−1; H NMR (300 MHz, CDCl3)
J
1
H-6b), 4.30–4.18 (m, 4H, 2 CH2CH3), 3.96 (ddd, 1H,
H-5), 3.29, 3.08 (each s, each 6H, 4 Ms), 1.33, 1.31
(each t, each 3H, JH,H=7.0, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 167.6 (CO chelated), 165.0 (CO
free), 156.8 (HCꢁ), 96.1 (ꢁC), 86.5 (C-1), 76.8 (C-3),
76.0 (C-2), 73.1 (C-5), 71.9 (C-4), 66.6 (C-6), 60.6, 60.3
(2 CH2CH3), 39.3, 39.2, 38.9, 37.6 (4 Ms), 14.1, 14.0 (2
CH2CH3). Anal calcd for C18H31NO17S4: C, 32.67; H,
4.72; N, 2.12. Found: C, 32.79; H, 4.72; N, 2.23%.
l 9.40 (dd, 1H, JNH,1=9.8, JNH,HCꢁ=12.9, NH), 8.17–
7.16 (m, 15H, 3 Ph), 7.98 (d, 1H, HCꢁ), 5.99 (t, 1H,
J2,3=J3,4=9.8, H-3), 5.57 (t, 1H, J4,5=9.8, H-4), 5.55
(t, 1H, J1,2=9.8, H-2), 4.87 (t, 1H, H-1), 4.46–4.42 (m,
1H, H-6a), 4.41 (m, 1H, H-5), 4.33–4.14 (m, 5H, H-6b,
2 CH2CH3), 3.04 (s, 3H, Ms), 1.33, 1.27 (each t, each
3H, JH,H=7.1, 2 CH2CH3); 13C NMR (125.7 MHz,
CDCl3) l 167.3, 165.5, 165.3, 165.2, 165.1 (5 CO), 156.9
(HCꢁ), 133.7–125.2 (18 C, 3 Ph), 95.5 (ꢁC), 87.3 (C-1),
73.9 (C-3), 72.3 (C-2), 70.9 (C-5), 68.5 (C-4), 66.8 (C-6),
60.3, 60.1 (2 CH2CH3), 37.6 (Ms), 14.2, 14.1 (2
CH2CH3). Anal. calcd for C36H37NO14S: C, 58.45; H,
5.04; N, 1.89. Found: C, 58.41; H, 5.05; N, 1.93%.
4.2.2. N-(2,2-Diethoxycarbonylvinyl)-2,3,4-6-tetra-O-
mesyl-b-D-galactopyranosylamine, 5. m=1.00 g (2.86
mmol); x=1.56 mL (17.2 mmol); y=40 mL; t=3.0 h.
Column chromatography (EtOAc/hexane, 1:1) gave 5
as an amorphous solid. Yield 97%. [h]2D6 +4 (c 1.0,
CH2Cl2); FABMS m/z 684 [(M+Na)+]; IR 3285, 3032,
4.2.5. 2,3,4-Tri-O-acetyl-N-(2,2-diethoxycarbonylvinyl)-
1
6-O-mesyl-b-
D
-glucopyranosylamine, 10. m=0.22
g
2944, 1699, 1616, 1371, 1179, 1071, 970, 831 cm−1; H
(0.46 mmol); x=0.1 mL (1.10 mmol); y=6.5 mL; t=
12.0 h. Column chromatography (ether/hexane, 12:1)
gave 10 as an amorphous solid. Yield 72%; [h]2D8 −4 (c
1.0, CH2Cl2); FABMS m/z 576 [(M+Na)+]; IR 2980,
1753, 1697, 1655, 1613, 1373, 1223, 1038, 907, 802
cm−1; 1H NMR (300 MHz, CDCl3) l 9.20 (dd, 1H,
NMR (500 MHz, CDCl3) l 9.39 (dd, 1H, JNH,1=9.0,
J
NH,HCꢁ=12.8, NH), 7.98 (d, 1H, HCꢁ), 5.33 (d, 1H,
J3,4=3.2, H-4), 5.02 (dd, 1H, J2,3=9.9, H-3), 4.88 (m,
1H, H-2), 4.74 (t, 1H, J1,2=9.0, H-1), 4.37 (m, 1H,
H-6a), 4.32 (m, 1H, H-6b), 4.30–4.19 (m, 5H, H-5, 2
CH2CH3), 3.29, 3.24, 3.08, 3.07 (each, s, 3H, 4 Ms),
1.33, 1.30 (each t, 3H, JH,H=7.1, 2 CH2CH3); 13C
NMR (500 MHz, CDCl3, l ppm, J Hz) l 168.0 (CO
chelated), 165.2 (CO free), 157.1 (HCꢁ), 95.9 (ꢁC), 86.8
(C-1), 75.5 (C-5), 75.3 (C-3), 74.8 (C-2), 72.2 (C-4), 65.9
(C-6), 60.6, 60.4 (2 CH2CH3), 39.4, 39.1, 39.0, 37.6 (4
Ms), 14.2, 14.1 (2 CH2CH3). Anal. calcd for
C18H31NO17S4: C, 32.67; H, 4.72; N, 2.12. Found: C,
32.89; H, 4.69; N, 2.12%.
J
NH,1=8.9, JNH,HCꢁ=13.1, NH), 7.93 (d, 1H, HCꢁ),
5.33 (t, 1H, J2,3=J3,4=9.6, H-3), 5.18–5.02 (m, 2H,
H-2, H-4), 4.57 (t, 1H, J1,2=8.9, H-1), 4.33–4.16 (m,
5H, H-5, 2 CH2CH3), 3.76 (m, 1H, H-6a), 3.61 (m, 1H,
H-6b), 3.04 (s, 3H, Ms), 2.07, 2.03, 2.02 (each s, each
3H, 3 Ac), 1.32, 1.29 (each t, each 3H, JH,H=7.1, 2
CH2CH3); 13C NMR (75.5 MHz, CDCl3) l 170.0 (2 C,
2 CO), 169.5, 167.5, 165.5 (3 CO), 157.2 (HCꢁ), 94.8
(ꢁC), 87.0 (C-1), 73.4 (C-3), 72.2 (C-2), 70.2 (C-5), 67.7
(C-4), 66.0 (C-6), 60.3, 60.1 (2 CH2CH3), 37.6 (Ms),
20.5 (2 C, 2 Ac), 20.4 (Ac), 14.2, 14.1 (2 CH2CH3).
Anal. calcd for C21H31NO14S: C, 45.56; H, 5.64; N,
2.53. Found: C, 45.83; H, 5.65; N, 2.54%.
4.2.3.
mesyl-b-
N-(2,2-Diethoxycarbonylvinyl)-2,3,4-6-tetra-O-
-manopyranosylamine, 6. m=1.00 (2.86
D
g
mmol); x=1.56 mL (17.2 mmol); y=40 mL; t=3.0 h.
Column chromatography (EtOAc/hexane, 2:1) gave 6
as an amorphous solid. Yield 95%. [h]2D6 −9 (c 1.0,
CH2Cl2); FABMS m/z 684 [(M+Na)+]; IR 3358, 3287,
3032, 2944, 1717, 1651, 1456, 1373, 1260, 1179, 1086,
4.2.6.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
-galactopyranosylamine, 13. m=
vinyl)-6-O-mesyl-b-
D
1
1024, 801, 754 cm−1; H NMR (300 MHz, CDCl3) l
1.18 g (1.78 mmol); x=0.41 mL (4.40 mmol); y=53.10
mL; t=24 h. Column chromatography (toluene/
methanol, 9:1) gave 13 as an amorphous solid. Yield
92%; [h]2D8 +7 (c 1.0, CH2Cl2); FABMS m/z 762 [(M+
Na)+]; IR 3289, 2980, 1736, 1657, 1613, 1452, 1366,
9.49 (dd, 1H, JNH,1=9.2, JNH,HCꢁ=13.0, NH), 8.01 (d,
1H, HCꢁ), 5.33 (dd, 1H, J1,2=0.8, J2,3=3.1, H-2), 5.08
(dd, 1H, J3,4=9.7, H-3), 5.03 (dd, 1H, H-1), 4.86 (t, 1H,
J
4,5=9.7, H-4), 4.61 (dd, 1H, J5,6a=2.2, J6a,6b=11.7,
1
H-6a), 4.40 (dd, 1H, J5,6b=5.0, H-6b), 4.23, 4.19 (each,
q, 2H, JH,H=7.1, 2 CH2CH3), 3.99 (ddd, 1H, H-5),
3.35, 3.26, 3.21, 3.08 (each, s, 3H, 4 Ms), 1.31, 1.29
(each, t, 3H, 2 CH2CH3); 13C NMR (75.4 MHz, CDCl3)
l 168.0, 165.3 (2 CO), 156.7 (HCꢁ), 95.2 (ꢁC), 84.0
(C-1), 76.6 (C-2), 73.9 (C-3), 73.4 (C-5), 70.6 (C-4), 67.0
(C-6), 60.4, 60.3 (2 CH2CH3), 39.1 (Ms), 39.0 (2 C, 2
1283, 1069, 1026, 801, 708 cm−1; H NMR (500 MHz,
CDCl3) l 9.51 (dd, 1H, JNH,1=8.9, JNH,HCꢁ=13.0,
NH), 8.09–7.23 (m, 15H, 3 Ph), 8.01 (d, 1H, HCꢁ), 5.97
(d, 1H, J3,4=3.3, H-4), 5.81 (dd, 1H, J1,2=8.9, J2,3
=
10.1, H-2), 5.72 (dd, 1H, H-3), 4.86 (t, 1H, H-1),
4.42–4.32 (m, 3H, H-5, H-6a, H-6b) 4.33–4.30, 4.17
(each q, each 2H, JH,H=7.1, 2 CH2CH3), 3.01 (s, 3H,

J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
1749
Ms), 1.34, 1.23 (each t, each 3H, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 167.7, 165.5, 165.4, 165.3, 165.2
(5 CO), 157.2 (HCꢁ), 133.7–125.2 (18 C, 3 Ph), 95.2
(ꢁC), 87.9 (C-1), 73.3 (C-5), 71.2 (C-3), 68.9 (C-2), 67.7
(C-4), 66.0 (C-6), 60.3, 60.1 (2 CH2CH3), 37.6 (Ms),
14.3, 14.2 (2 CH2CH3). Anal. calcd for C36H37NO14S:
C, 58.45; H, 5.04; N, 1.89. Found: C, 58.05; H, 5.07; N,
2.18%.
(C(Ph)3), 87.1 (C-1), 74.4 (C-5), 71.5 (C-3), 69.3 (C-2),
67.8 (C-4), 60.5 (C-6), 60.2, 60.0 (2 CH2CH3), 14.3, 14.2
(2 CH2CH3). Anal. calcd for C54H49NO12: C, 71.75; H,
5.46; N, 1.55. Found: C, 71.50; H, 5.50; N, 1.81%.
4.3.2.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
vinyl)-6-O-trityl-b-D-mannopyranosylamine, 14. Yield
90%; [h]2D0 −41 (c 1.1, CH2Cl2); FABMS m/z 926 [(M+
Na)+]; IR 3288, 3061, 2982, 2934, 1774, 1699, 1651,
1
4.2.7.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
-manopyranosylamine, 16. m=1.30
1616, 1454, 1271, 1103, 1067, 1026, 706 cm−1; H NMR
vinyl)-6-O-mesyl-b-
D
(300 MHz, CDCl3) l 9.56 (dd, J1,NH=8.0, JNH, ꢁCH=
13.3, 1H, NH), 8.24 (d, 1H, HCꢁ), 8.17–7.10 (m, 30H,
6 Ph), 6.17 (t, J3,4=J4,5=10.2, 1H, H-4), 5.98 (dd,
g (1.97 mmol); x=0.43 mL (4.73 mmol); y=59.1 mL;
t=24 h. Column chromatography (toluene/methanol,
9:1) gave 16 as an amorphous solid. Yield 89%; [h]D28
−39 (c 1.0, CH2Cl2); FABMS m/z 762 [(M+Na)+]; IR
3067, 2980, 2932, 1728, 1620, 1452, 1381, 1287, 1061,
J
1,2=1.1, J2,3=3.1, 1H, H-2), 5.55 (dd, 1H, H-3), 5.11
(dd, 1H, H-1), 4.17–4.08 (m, 4H, 2 CH2CH3), 3.90
(ddd, J5,6a=2.2, J5,6b=3.5, 1H, H-5), 3.54 (dd, J6a,6b
=
1
1021, 801, 702 cm−1; H NMR (500 MHz, CDCl3) l
10.7, 1H, H-6a), 3.26 (dd, 1H, H-6b), 1.22, 1.18 (each t,
each 3H, JH,H=7.1, 2 CH2CH3); 13C NMR (75.5 MHz,
CDCl3) l 167.7, 165.5 (2 C), 165.3, 164.7 (5 CO), 156.6
(HCꢁ), 143.4–126.8 (6 Ph), 93.9 (ꢁC), 86.6 (C(Ph)3),
84.4 (C-1), 75.9 (C-5), 72.4 (C-3), 70.2 (C-2), 65.6 (C-4),
61.8 (C-6), 60.0, 59.8 (2 CH2CH3), 14.2, 14.1 (2
CH2CH3). Anal. calcd for C54H49NO12: C, 71.75; H,
5.46; N, 1.55. Found: C, 72.03; H, 5.54; N, 1.57%.
9.51 (dd, 1H, JNH,1=8.8, JNH,HCꢁ=13.0, NH), 8.10 (d,
1H, HCꢁ), 8.08–7.26 (m, 15H, 3 Ph), 5.98 (dd, 1H,
J1,2=1.1, H-2), 5.79 (t, 1H, J3,4=J4,5=10.0, H-4), 5.68
(dd, J2,3=3.1, 1H, H-3), 5.16 (dd, 1H, H-1), 4.48–4.47
(m, 2H, H-6a, H-6b), 4.20 (m, 1H, H-5), 4.19, 4.10
(each m, each 2H, 2 CH2CH3), 3.05 (s, 3H, Ms), 1.29,
1.19 (each t, each 3H, JH,H=7.0, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 167.6, 165.5, 165.3 (2 C), 165.2
(5 CO), 156.6 (HCꢁ), 133.9–128.4 (18 C, 3 Ph), 94.9
(ꢁC), 84.8 (C-1), 74.1 (C-5), 71.7 (C-3), 69.8 (C-2), 67.5
(C-6), 65.8 (C-4), 60.2, 60.1 (2 CH2CH3), 37.7 (Ms),
14.3, 14.1 (2 CH2CH3). Anal. calcd for C36H37NO14S:
C, 58.45; H, 5.04; N, 1.89. Found: C, 58.11; H, 5.02; N,
1.82%.
4.4. Procedure for the preparation of compounds 12, 15
A cooled (0°C) solution of the corresponding trityl
derivatives 11, 14 (2.76 g, 3.06 mmol) in F3CCOOH/
H2O (3:1) (44 mL) was stirred for 5 min and then
neutralized with sodium hydrogen carbonate and
extracted with CH2Cl2. The organic layer was sepa-
rated, washed with water, dried (MgSO4), filtered, and
evaporated to dryness. The residue was purified by
column chromatography (toluene/methanol, 9:1).
4.3. Preparation of compounds 11 and 14
To a stirred solution of the corresponding N-(2,2-
diethoxycarbonylvinyl)-b- -glycopyranosylamine 2 and
D
3 (3.10 g, 8.88 mmol) in dry pyridine (16 mL), trityl
chloride (2.7 mL, 9.69 mmol) was added. The mixture
was heated for 24 h at 50°C, then cooled to 0°C and
benzoyl chloride (2.40 g, 20.64 mmol) was added drop-
wise. The solution was stirred at rt for 24 h, then
poured into ice-water and extracted with CH2Cl2. The
combined extracts were washed with 1 M H2SO4, satd
aq. NaHCO3, and water, dried (MgSO4) and evapo-
rated to dryness. Column chromatography (EtOAc/
hexane, 1:2) gave 11 and 14, respectively, as amorphous
solids.
4.4.1.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
D-galactopyranosylamine, 12. Amorphous solid;
vinyl)-b-
yield 83%; [h]2D0 +5 (c 1.1, CH2Cl2); EIMS m/z 662
(M+); IR 3482, 3065, 2980, 2938, 1736, 1613, 1452,
1260, 1101, 801, 710 cm−1; 1H NMR (300 MHz, CDCl3)
l 9.50 (dd, J1,NH=8.9 JNH, =CH=13.2, 1H, NH), 8.13–
7.22 (m, 15H, 3 Ph), 8.02 (d, 1H, HCꢁ), 5.88 (d,
J3,4=3.3, 1H, H-4), 5.86 (dd, J1,2=8.9, J2,3=10.3, 1H,
H-2), 5.73 (dd, 1H, H-3), 4.85 (t, 1H, H-1), 4.26, 4.15
(each q, each 2H, JH,H=7.1, CH2CH3), 4.19–4.04 (m,
1H, H-5), 3.84 (dd, J5,6a=6.6, J6a,6b=11.9, 1H, H-6a),
3.65 (dd, J5,6b=6.7, 1H, H-6b), 1.33, 1.25 (each t, each
3H, 2 CH2CH3); 13C NMR (75.5 MHz, CDCl3) l 167.6,
166.4, 165.5, 165.3, 165.2 (5 CO), 157.5 (HCꢁ), 133.8–
128.2 (3 Ph), 94.6 (ꢁC), 87.8 (C-1), 75.8 (C-5), 71.4
(C-3), 69.3 (C-2), 68.6 (C-4), 60.4 (C-6), 60.2, 60.0 (2
CH2CH3), 14.2, 14.1 (2 CH2CH3). Anal. calcd for
C35H35NO12: C, 63.53; H, 5.33; N, 2.12. Found: C,
63.20; H, 5.42; N, 2.20%.
4.3.1.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
vinyl)-6-O-trityl-b-D-galactopyranosylamine, 11. Yield
91%; [h]2D0 +20 (c 0.8, CH2Cl2); FABMS m/z 926 [(M+
Na)+]; IR 3298, 3032, 2980, 2938, 1732, 1719, 1705,
1616, 1451, 1282, 1279, 1096, 1071, 706 cm−1; H NMR
1
(500 MHz, CDCl3) l 9.39 (dd, J1,NH=8.7, JNH, ꢁCH
=
13.3, 1H, NH), 7.99 (d, 1H, HCꢁ), 7.93–7.12 (m, 30H,
6 Ph), 6.13 (dd, J3,4=3.3, J4,5=1.1, 1H, H-4), 5.75 (dd,
J
2,3=10.3, 1H, H-3), 5.66 (dd, J1,2=8.7, 1H, H-2), 4.75
4.4.2.
2,3,4-Tri-O-benzoyl-N-(2,2-diethoxycarbonyl-
(t, 1H, H-1), 4.26 (q, JH,H=7.1, 2H, CH2CH3), 4.18–
4.09 (m, 3H, H-5, CH2CH3), 3.47 (dd, J5,6a=5.4,
vinyl)-b-D-mannopyranosylamine, 15. Amorphous solid;
yield 98%; [h]2D0 −44 (c 1.1, CH2Cl2); FABMS m/z 684
(M+Na)+; IR 3281, 3065, 2980, 2876, 1732, 1678, 1609,
J
6a,6b=9.0, 1H, H-6a), 3.26 (t, J5,6b=9.0, 1H, H-6b),
1.26, 1.24 (each t, each 3H, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 167.5, 165.4, 165.5, 165.1 (5
CO), 157.4 (HCꢁ), 143.1–127.0 (6 Ph), 94.6 (ꢁC), 87.8
1452, 1258, 1069, 1028, 710 cm−1; H NMR (300 MHz,
1
CDCl3) l 9.48 (dd, J1,NH=8.9 JNH, =CH=13.2, 1H,
NH), 8.11 (d, 1H, HCꢁ), 8.10–7.29 (m, 15H, 3 Ph),

1750
J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
5.97 (dd, J1,2=1.1, J2,3=3.0, 1H, H-2), 5.78 (t, J3,4
4,5=10.1, 1H, H-4), 5.72 (dd, 1H, H-3), 4.13 (dd, 1H,
H-1), 4.23–4.04 (m, 4H, 2 CH2CH3), 3.92–3.78 (m, 3H,
=
calcd for C35H33NO11: C, 65.31; H, 5.17; N, 2.18.
Found: C, 64.87; H, 4.98; N, 2.30%.
J
H-5, H-6a, H-6b), 1.28, 1.17 (each t, each 3H, JH,H
=
4.5.3. 1,6-Anhydro-2,3,4-tri-O-acetyl-N-(2,2-diethoxy-
carbonylvinyl)-b-D-glucopyranosylamine, 20. Column
7.1, 2 CH2CH3); 13C NMR (75.5 MHz, CDCl3) l 167.4,
166.0, 165.5, 165.4 (2 C) (5 CO), 156.7 (HCꢁ), 133.7–
128.2 (3 Ph), 94.5 (ꢁC), 85.0 (C-1), 76.6 (C-5), 71.6
(C-3), 69.9 (C-2), 66.1 (C-4), 61.3 (C-6), 60.1, 60.0 (2
CH2CH3), 14.2, 14.0 (2 CH2CH3). Anal. calcd for
C35H35NO12: C, 63.53; H, 5.33; N, 2.12. Found: C,
63.52; H, 5.29; N, 2.10%.
chromatography (ether/hexane, 12:1) gave 20 as an
amorphous solid. Yield 80%; [h]2D8 −135 (c 1.1, CH2Cl2);
FABMS m/z 480 [(M+Na)+]; IR 2984, 1746, 1605,
1371, 1221, 1163, 1047 cm−1; 1H NMR (500 MHz,
CDCl3) l 7.62 (s, 1H, HCꢁ), 5.38 (bs, 1H, H-1), 4.86
(m, 1H, H-3), 4.73 (d, 1H, J5,6b=6.7, H-5), 4.66 (m, 2H,
H-2, H-4), 4.29–4.15 (m, 4H, 2 CH2CH3), 3.61 (d, 1H,
4.5. General procedure for the preparation of com-
pounds 17, 18, 20, 21, 22, 24, and 25
J6a,6b=10.7, H-6a), 3.40 (dd, 1H, H-6b), 2.17 (s, 6H, 2
Ac), 2.14 (s, 3H, Ac), 1.32, 1.27 (each, t, 3H, JH,H=7.1,
2 CH2CH3); 13C NMR (125.7 MHz, CDCl3) l 169.7,
169.4, 168.9, 166.4, 166.3 (5 CO), 144.0 (HCꢁ), 97.7
(ꢁC), 89.0 (C-1), 75.6 (C-5), 69.2 (C-4), 68.4 (C-3), 68.2
(C-2), 60.8, 60.3 (2 CH2CH3), 47.7 (C-6), 20.8, 20.7,
20.4 (3 Ac), 14.2, 14.1 (2 CH2CH3). Anal. calcd for
C20H27NO11: C, 52.51; H, 5.95; N, 3.06. Found: C,
52.59; H, 6.14; N, 3.05%.
To a stirred solution of the corresponding 6-O-mesyl-
ated N-diethoxycarbonylvinyl-D-glycopyranosylamines
4, 5, 6, 9, 10, 13, and 16 (273 g, 0.37 mmol) in DMF
(4.8 mL) at 40°C, 20 mmHg of sodium methoxide (21
mg, 0.37 mmol) was added. The reaction was stirred for
15 min and controlled by TLC (CH2Cl2/MeOH, 70:1).
The mixture was added to ice-water and extracted with
CH2Cl2. The organic layer was separated, washed with
1 M sulphuric acid, saturated aqueous sodium hydro-
gencarbonate, and water, dried (MgSO4), filtered, and
evaporated to dryness. The residue was purified by
column chromatography.
4.5.4. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-2,3,4-
tri-O-mesyl-b-D-galactopyranosylamine, 21. Column
chromatography (EtAcO/hexane, 3:1) gave 21 as an
amorphous solid. Yield 69%; [h]2D6 −19 (c 1.1, CH2Cl2);
FABMS m/z 588 [(M+Na)+]; IR 3362, 2907, 2807,
1
1715, 1456, 1373, 1086, 1024 y 746 cm−1; H NMR (300
4.5.1. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-2,3,4-
MHz, CDCl3) l 7.56 (s, 1H, HCꢁ), 5.49 (bs, 1H, H-1),
5.18 (m, 1H, H-3), 5.12 (t, 1H, J3,4=J4,5=4.5, H-4),
4.95 (bs, 1H, H-2), 4.78 (m, 1H, H-5), 4.28–4.15 (m,
4H, 2 CH2CH3), 3.89 (l, 1H, J6a,6b=10.5, H-6a), 3.41
(m, 1H, H-6b), 3.22, 3.21, 3.19 (each, s, 3H, 3 Ms),
1.38–1.25 (m, 6H, 2 CH2CH3); 13C NMR (75.4 MHz,
CDCl3) l 166.5, 166.1 (2 CO), 145.0 (HCꢁ), 98.5 (ꢁC),
87.9 (C-1), 74.5 (C-5), 74.3 (C-2), 72.1 (C-3), 67.3 (C-4),
61.1, 60.6 (2 CH2CH3), 47.5 (C-6), 38.8, 38.3 (2 Ms),
14.1, 14.0 (2 CH2CH3). HRCIMS calcd for
C17H28NO14S3: 566.0672. Found 566.0682.
tri-O-mesyl-b-D-glucopyranosylamine, 17. Column chro-
matography (toluene/EtOAc, 2:1) gave 17 as an
amorphous solid. Yield 70%; [h]2D2 −33 (c 1.0, CH2Cl2);
FABMS m/z 588 [(M+Na)+]; IR 3027, 2942, 1707,
1607, 1366, 1179, 959, 816 cm−1; 1H NMR l (500 MHz,
CDCl3) 7.59 (s, 1H, HCꢁ), 5.55 (bs, 1H, H-1), 5.00 (m,
1H, H-3), 4.92 (d, 1H, J5,6b=6.5, H-5), 4.76 (m, 2H,
H-2, H-4), 4.31–4.18 (m, 4H, 2 CH2CH3), 3.71 (d, 1H,
J
6a,6b=10.7, H-6a), 3.48 (m, 1H, H-6b), 3.23, 3.22, 3.20
(each s, each 3H, 3 Ac), 1.32, 1.28 (each t, each 3H,
H,H=7.1, 2 CH2CH3); 13C NMR (75.5 MHz, CDCl3) l
J
166.5, 166.1 (2 CO), 144.9 (HCꢁ), 98.7 (ꢁC), 88.6 (C-1),
75.6 (C-5), 73.6 (C-4), 72.6 (C-3), 72.0 (C-2), 61.1, 60.6
(2 CH2CH3), 48.4 (C-6), 38.6, 38.5, 38.4 (3 Ms), 14.2,
14.0 (2 CH2CH3). Anal. calcd for C17H27NO14S3: C,
36.10; H, 4.81; N, 2.48; S, 17.00. Found: C, 36.27; H,
4.70; N, 2.67; S, 17.26%.
4.5.5. 1,6-Anhydro-2,3,4-tri-O-benzoyl-N-(2,2-diethoxy-
carbonylvinyl)-b-D-galactopyranosylamine, 22. Column
chromatography (EtAcO/hexane, 2:1) gave 22 as an
amorphous solid. Yield 80%; [h]2D6 +5 (c 0.7, CH2Cl2);
FABMS m/z 666 [(M+Na)+]; IR 3063, 2980, 1736,
1691, 1601, 1452, 1260, 1163, 1096, 1024, 878, 708
cm−1; 1H NMR (500 MHz, CDCl3) l 8.14–7.26 (m,
15H, 3 Ph), 7.84 (s, 1H, HCꢁ), 5.91 (dd, 1H, J2,3=1.3,
4.5.2. 1,6-Anhydro-2,3,4-tri-O-benzoyl-N-(2,2-diethoxy-
carbonylvinyl)-b-
D
-glucopyranosylamine, 18. Column
J3,4=5.5, H-3), 5.74 (m, 1H, H-4), 5.59 (s, 1H, H-1),
chromatography (CH2Cl2/MeOH, 100:1) gave 18 as a
solid. Yield 80%; mp 166–168 (ether–hexane); [h]2D6 −69
(c 1.0, CH2Cl2); FABMS m/z 666 [(M+Na)+]; IR 2961,
5.32 (d, 1H, H-2), 4.88 (m, 1H, H-5), 4.32–4.19 (m, 4H,
2 CH2CH3), 3.00 (d, 1H, J6a,6b=10.5, H-6a), 3.63 (dd,
J
5,6b=6.4 H, H-6b), 1.34, 1.28 (each t, each 3H, JH,H=
1717, 1699, 1364, 1262, 1088, 1026, 710 cm−1; H NMR
7.1, 2 CH2CH3); 13C NMR (125.7 MHz, CDCl3) l
166.5, 166.3, 165.1, 164.9, 164.8 (5 CO), 144.7 (HCꢁ),
133.8–128.3 (18 C, 3 Ph), 97.6 (ꢁC), 89.3 (C-1), 74.1
(C-5), 71.3 (C-2), 67.3 (C-3), 65.2 (C-4), 60.8, 60.3 (2
CH2CH3), 47.3 (C-6), 14.3, 14.2 (2 CH2CH3). Anal.
calcd for C35H33NO11: C, 65.31; H, 5.17; N, 2.18.
Found: C, 64.94; H, 5.54; N, 2.20%.
1
(500 MHz, CDCl3) l 8.17–7.27 (m, 15H, 3 Ph), 7.84 (s,
1H, HC=), 5.65 (s, 1H, H-1), 5.54 (s, 1H, H-3), 5.14 (s,
1H, H-2), 5.08 (s, 1H, H-4), 4.99 (d, 1H, J5,6b=6.4,
H-5), 4.31–4.18 (m, 4H, 2 CH2CH3), 3.82 (d, 1H,
J
6a,6b=10.9, H-6a), 3.70 (dd, 1H, H-6b), 1.33–1.26 (m,
6H, 2 CH2CH3); 13C NMR (125.7 MHz, CDCl3) l
166.4, 166.2, 165.1, 165.0, 164.5 (5 CO), 144.6 (HCꢁ),
133.7–127.8 (18 C, 3 Ph), 97.8 (ꢁC), 89.4 (C-1), 75.7
(C-5), 69.6 (C-4), 68.8 (2 C, C-2, C-3), 60.9, 60.3 (2
CH2CH3), 48.1 (C-6), 14.3, 14.1 (2 CH2CH3). Anal.
4.5.6. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-2,3,4-
tri-O-mesyl-b-D-mannopyranosylamine, 24. Column
chromatography (EtAcO/hexane, 2:1) gave 24 as an

J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
1751
amorphous solid. Yield 68%; [h]2D8 −113 (c 1.0, CH2Cl2);
FABMS m/z 588 [(M+Na)+]; IR 3412, 3025, 2938,
1692, 1607, 1466, 1366, 1267, 1177, 1090, 1030, 964,
(C-4), 71.6 (C-2), 61.9, 61.2 (2 CH2CH3), 49.5–48.5
(C-6), 14.7, 14.5 (2 CH2CH3). Anal. calcd for
C14H21NO8: C, 50.75; H, 6.39; N, 4.23. Found: C,
50.36; H, 6.43; N, 4.19%.
1
851, 741 cm−1; H NMR (500 MHz, CDCl3) l 7.64 (s,
1H, HCꢁ), 5.43 (bs, 1H, H-1), 5.20 (m, 1H, H-3), 5.01
(dd, 1H, J1,2=2.4, J2,3=5.1, H-2), 4.95 (m, 1H, H-4),
4.90 (d, 1H, J5,6b=6.9, H-5), 4.27–4.16 (m, 4H, 2
CH2CH3), 3.74 (d, 1H, J6a,6b=11.1, H-6a), 3.36 (dd,
1H, H-6b), 3.25, 3.20, 3.19 (each, s, 3H, 3 Ms), 1.32,
1.27 (each, t, 3H, JH,H=7.1, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 166.4, 166.3 (2 CO), 144.4
(HCꢁ), 98.2 (ꢁC), 89.5 (C-1), 76.4 (C-5), 76.1 (C-4), 71.5
(C-3), 69.7 (C-2), 61.0, 60.4 (2 CH2CH3), 47.1 (C-6),
38.7, 38.6, 38.5 (3 Ms), 14.2, 14.1 (2 CH2CH3). Anal.
calcd for C17H27NO14S3: C, 36.10; H, 4.81; N, 2.48.
Found: C, 36.45; H, 4.97; N, 2.39%.
4.6.2. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-b-D-
galactopyranosylamine, 23. 97%; amorphous solid; [h]D26
−54 (c 1.0, MeOH); FABMS m/z 354 [(M+Na)+]; IR
3410, 2982, 2903, 1697, 1605, 1393, 1275, 1208, 1099,
1
1072, 866, 758 cm−1; H NMR (500 MHz, MeOD) l
7.72 (s, 1H, HCꢁ), 5.24 (bs, 1H, H-1), 4.41 (m, 1H,
H-5), 4.20, 4.13 (each q, each 2H, JH,H=7.1, 2
CH2CH3), 3.96 (t, 1H, J3,4=J4,5=4.6, H-4), 3.87 (m,
1H, H-3), 3.80 (bs, 1H, H-2), 3.70 (m, 1H, H-6a), 3.33
(m, 1H, H-6b), 1.29, 1.24 (each t, each 3H, 2 CH2CH3);
13C NMR (125.7 MHz, CDCl3) l 169.2, 168.9 (2 CO),
147.6 (HCꢁ), 95.3 (ꢁC), 92.6 (C-1), 78.1 (C-5), 72.8
(C-2), 72.1 (C-3), 65.4 (C-4), 61.8, 61.1 (2 CH2CH3),
48.5 (C-6), 14.7, 14.5 (2 CH2CH3). HREIMS calcd for
C14H21NO8: 331.1267. Found 331.1263. Anal. calcd for
C14H21NO8: C, 50.75; H, 6.39; N, 4.23. Found: C,
50.35; H, 6.51; N, 4.26%.
4.5.7. 1,6-Anhydro-2,3,4-tri-O-benzoyl-N-(2,2-diethoxy-
carbonylvinyl)-b-D-mannopyranosylamine, 25. Column
chromatography (ether/hexane, 1:1) gave 25 as an
amorphous solid. Yield 93%; [h]2D1 −2 (c 0.7, CH2Cl2);
FABMS m/z 666 [(M+Na)+]; IR 3063, 2980, 2903,
1726, 1682, 1601, 1452, 1263, 1206, 1107, 1024, 856, 708
cm−1; 1H NMR (500 MHz, CDCl3) l 8.15–7.26 (m,
15H, 3 Ph), 7.84 (s, 1H, HCꢁ), 5.93 (d, J2,3=5.3, 1H,
H-3), 5.67 (d, 1H, H-2), 5.50 (bs, 1H, H-1), 5.28 (bs,
1H, H-4), 4.97 (d, 1H, J5,6b=6.5, H-5), 4.29 (q, 2H,
4.6.3. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-b-D-
mannopyranosylamine, 26. 97%; amorphous solid; [h]D21
−138 (c 0.66, MeOH); FABMS m/z 354 [(M+Na)+]; IR
3376, 2980, 2907, 1674, 1597, 1379, 1275, 1209, 1078,
JH,H=7.1, CH2CH3), 4.16–4.07 (m, 2H, CH2CH3), 3.87
1
1038, 866, 766 cm−1; H NMR (500 MHz, MeOD) l
(d, 1H, J6a,6b=10.9, H-6a), 3.82 (dd, 1H, H-6b), 1.29,
1.14 (each t, each 3H, 2 CH2CH3); 13C NMR (125.7
MHz, CDCl3) l 166.7, 166.3, 165.2, 165.0, 164.8 (5
CO), 144.8 (HCꢁ), 133.7–128.3 (18 C, 3 Ph), 97.0 (ꢁC),
89.5 (C-1), 76.3 (C-5), 72.2 (C-4), 67.6 (C-3), 67.5 (C-2),
60.9, 60.0 (2 CH2CH3), 47.6 (C-6), 14.3, 14.2 (2
CH2CH3). Anal. calcd for C35H33NO11: C, 65.31; H,
5.17; N, 2.18. Found: C, 65.03; H, 5.07; N, 2.37%.
7.80 (s, 1H, HCꢁ), 5.13 (bs, 1H, H-1), 4.55 (m, 1H,
J
5,6b=7.1, H-5), 4.19, 4.13 (each q, each 2H, JH,H=7.1,
2 CH2CH3), 3.88 (m, 2H, H-2, H-3), 3.77 (bs, 1H, H-4),
3.62 (d, 1H, J6a,6b=10.5, H-6a), 3.26 (dd, 1H, H-6b),
1.29, 1.24 (each t, each 3H, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 169.4, 169.2 (2 CO), 148.1
(HCꢁ), 95.0 (ꢁC), 93.7 (C-1), 79.5 (C-5), 73.1 (C-4), 71.9
(C-2), 67.1 (C-3), 61.9, 61.2 (2 CH2CH3), 48.5 (C-6),
14.7, 14.5 (2 CH2CH3). HREIMS calcd for C14H21NO8:
331.1267. Found 331.1268. Anal. calcd for C14H21NO8:
C, 50.75; H, 6.39; N, 4.23. Found: C, 50.36; H, 6.28; N,
4.34%.
4.6. General procedure for the preparation of com-
pounds 19, 23, and 26
To a solution of the corresponding O-benzoylated (140
mg, 0.218 mmol) 18, 22, and 25 in anhydrous methanol
(41.3 mL), at rt under argon, was added NaMeO/
MeOH 1 M (104 mL). The process was controlled by
TLC CH2Cl2/MeOH (15:1) until total deacylation of
starting material. After 4 h, the reaction mixture was
neutralized with acid resin Amberlite IR-120(H+),
filtered and the solvent was evaporated to dryness. The
residue was purified by column chromatography
(CH2Cl2/MeOH, 15:1).
4.7. General procedure for the preparation of com-
pounds 27–29
To a solution of the corresponding 1,6-anhydro-N-(2,2-
diethoxycarbonylvinyl)-b-
D
-glycopyranosylamine
19,
23, 26 (38 mg, 0.115 mmol) in dichloromethane (14.0
mL), CH2Cl2 saturated with chlorine at 0°C was added.
The reaction mixture was kept for 15 min at 0°C until
total consumption of the starting material (TLC), and
evaporated, then washed with dry dichloromethane (2×
2.2 mL). The residue was dried and used without
further purification.
4.6.1. 1,6-Anhydro-N-(2,2-diethoxycarbonylvinyl)-b-D-
glucopyranosylamine, 19. Yield 90%; amorphous solid;
[h]2D6 −9 (c 1.0, CH2Cl2); FABMS m/z 354 [(M+Na)+];
IR 3391, 2980, 2932, 1697, 1597, 1395, 1275, 1208,
1096, 1045, 889, 735 cm−1; 1H NMR (500 MHz,
MeOD) l 7.74 (s, 1H, HCꢁ), 5.32 (bs, 1H, H-1), 4.58
(m, 1H, H-5), 4.19, 4.13 (each q, each 2H, JH,H=7.1, 2
CH2CH3), 3.57 (m, 1H, H-2), 3.70 (m, 1H, H-3), 3.54
(m, 1H, H-6a), 3.51 (m, 1H, H-4), 3.40 (m, 1H, H-6b),
1.28, 1.26 (each t, each 3H, 2 CH2CH3); 13C NMR
(125.7 MHz, CDCl3) l 169.1, 168.8 (2 CO), 147.5
(HCꢁ), 95.8 (ꢁC), 93.2 (C-1), 79.7 (C-5), 73.7 (C-3), 72.0
4.7.1. 1,6-Anhydro-b-
D-glucopyranosylamine, 27. Amor-
phous solid FABMS m/z 162 [(M+H)+].
4.7.2.
1,6-Anhydro-b-
D
-galactopyranosylamine,
28.
29.
Amorphous solid FABMS m/z 162 [(M+H)+].
4.7.3.
1,6-Anhydro-b-D-mannopyranosylamine,
Amorphous solid FABMS m/z 162 [(M+H)+].

1752
J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
4.8. General procedure for the preparation of compounds
33–35
References
1. For reviews see: (a) Legler, G. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 319–384; (b) Wong, C. H.; Halcomb,
R. L.; Ichikawa, Y.; Kajimoto, T. Angew. Chem., Int. Ed.
Engl. 1995, 34, 521–546; (b) Lillelund, V. H.; Jensen, H.
H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–553;
(c) Asano, N.; Oseki, H.; Kizu, H.; Matsui, K. J. Med.
Chem. 1994, 37, 3701–3706.
2. See as examples: (a) Kiess, F. M.; Poggendorf, P.;
Picasso, S.; Ja¨ger, V. Chem. Commun. 1998, 119–120; (b)
Blanco, M. J.; Sardina, F. J. J. Org. Chem. 1998, 63,
3411–3416; (c) Wehner, V.; Ja¨ger, V. Angew. Chem., Int.
Ed. Engl. 1990, 29, 1169–1171; (d) Kraehenbuehl, K.;
Picasso, S.; Vogel, P. Biorg. Med. Chem. Lett. 1997, 7,
893–896; (e) Fuentes, J.; Olano, D.; Pradera, M. A.
Tetrahedron: Asymmetry 1997, 8, 3443–3456; (f) Hum-
mer, W.; Dubois, E.; Gracza, T.; Ja¨ger, V. Synthesis
1997, 634–642; Farr, R. A.; Holland, A. K.; Huber, E.
W.; Peet, N. P.; Weintraub, P. M. Tetrahedron 1994, 50,
1033–1044.
A solution of the corresponding 1,6-anhydro com-
pound 27–29 (63 mg, 0.39 mmol) in acetic acid (3.5
mL) was treated with NaH3BCN (33 mg, 0.51 mmol).
The mixture was stirred for 24 h at rt and then evapo-
rated to dryness. The residue (tetrahydroxyazepinium
acetate, 30–32) was washed with dichloromethane,
filtered and purified by ion-exchange chromatography
(Dowex® 50 W-X8 NH4 form.) elude first with water
+
and then with a NH4OH gradient, 0“1N. The fractions
containing the product were concentrated.
4.8.1. (3R,4R,5R,6S)-3,4,5,6-Tetrahydroxyazepine, 33.
Yield 58%; [h]2D6 −7 (c 1.4, MeOH); EIMS m/z 163
+
’
[M ]; IR 3464, 2874, 1682, 1559, 1385, 1314, 1101,
1
1020, and 949 cm−1; H NMR (500 MHz, MeOD) l
3.92 (ddd, 1H, J5,6=1.8, J6,7a=6.0, J6,7b=3.3, H-6),
3.76 (dd, 1H, J3,4=5.6, J4,5=7.1, H-4), 3.68 (dd, 1H,
H-5), 3.57 (ddd, 1H, J2a,3=6.5, J2b,3=3.3, H-3), 2.98
(dd, 1H, J7a,7b=14.1, H-7a), 2.93 (dd, 1H, J2a,2b=14.3,
H-2a), 2.88 (dd, 1H, H-2b), and 2.84 (dd, 1H, H-7b);
13C NMR (125.7 MHz, MeOD) l 77.6 (C-5), 77.0
(C-4), 75.2 (C-3), 73.0 (C-6), 51.8 (C-7), and 50.9 (C-2),
HREIMS calcd for C6H13NO4: 163.0845. Found
163.0842.
3. See as examples: (a) Le Merrer, Y.; Poitout, L.; Depezay,
J. C.; Dosboa, I.; Geoffroy, S.; Foglietti, M. J. Bioorg.
Med. Chem. 1997, 5, 519–533; (b) Bauclat, A.; Vogel, P.
J. Org. Chem. 1997, 62, 6252–6260; (c) Jonson, C. R.;
Johns, B. A. J. Org. Chem. 1997, 62, 6046–6050; (d)
Hansen, A.; Tagmose, T. M.; Bols, M. Tetrahedron 1997,
53, 697–706.
4. (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. Engl. 1999, 38, 750–770 and references cited therein;
(b) Liu, J.; Shikhman, A. R.; Lotz, M. K.; Wong, C. H.
Chem. Biol. 2001, 8, 701–711; (c) Jeong, J. H.; Murray, B.
W.; Takayama, S.; Wong, C. H. J. Am. Chem. Soc. 1996,
118, 4227–4234; (d) Papandreou, G.; Tong, M. K.;
Ganem, B. J. J. Am. Chem. Soc. 1993, 115, 1682.
5. Moris Varas, F.; Aian, X. H.; Wong, C. H. J. Am. Chem.
Soc. 1996, 118, 7647–7652.
4.8.2. (3R,4S,5R,6S)-3,4,5,6-Tetrahydroxyazepine, 34.
Yield 58%; IR 3389, 2920, 1603, 1568, 1418, 1265, 1096,
1
1044, and 955 cm−1; H NMR (500 MHz, MeOD) l
3.96 (d, 2H, J3,4=6.3, H-4, H-5), 3.83 (m, 2H, H-3,
H-6), 3.15 (dd, 2H, J2b,3=J6,7b=4.0, J2a,2b=J7a,7b
=
14.3, H-2b, H-7b), 2.87 (dd, 2H, J2a,3=J6,7a=4.7, H-2a,
H-7a,); 13C NMR (125.7 MHz, MeOD) l 74.0 (C-4,
C-5), 69.9 (C-3, C-6), and 50.9 (C-2, C-7). HRCIMS
calcd for C6H14NO4: 164.0923. Found 164.0923.
6. Andersen, S. M.; Ekhart, C.; Lundt, I.; Stu¨tz, A. E.
Carbohydr. Res. 2000, 326, 22–33.
7. (a) Lohray, B. B.; Jayamma, Y.; Chatterjee, M. J. Org.
Chem. 1995, 60, 5958–5960; (b) Paulsen, H.; Todt, K.
Chem. Ber. 1967, 100, 512–520.
8. Long, D. D.; Stetz, R. E.; Nash, R. J.; Marquess, D. G.;
Lloyd, J. D.; Winters, A. L.; Asano, N.; Fleet, G. W. J.
J. Chem. Soc., Perkin Trans. 1 1999, 901–908.
9. Painter, G. F.; Falshaw, A. J. Chem. Soc., Perkin Trans.
1 2000, 1157–1159.
10. Le Merrer, Y.; Saniere, M.; McCort, I.; Dupuy, C.;
Depezay, J. C. Tetrahedron Lett. 2001, 42, 2661–2663.
11. (a) For the synthesis of hydroazepine analogues having
two nitrogen atoms in the ring, see: Ernholt, B. V.;
Thomson, I. B.; Jensen, K. B.; Bols, M. Synlett 1999,
701–704; (b) For bicyclic thiazoloazepine derivatives, see:
Mark, D.; Wadonachi, A.; Beaupere, D. Synthesis 1999,
839–843.
4.8.3. (3R,4R,5R,6R)-3,4,5,6-Tetrahydroxyazepine, 35.
Yield 58%; IR 3389, 2920, 1645, 1549, 1377, 1314, 1099,
1
1032, and 870 cm−1; H NMR (500 MHz, MeOD) l
4.13 (td, 2H, J2,3=J6,7=3.9, J3,4=J5,6=1.1, H-3, H-6),
3.81 (d, 2H, H-4, H-5), and 3.17 (d, 4H, H-2a, H-2b,
H-7a, H-7b); 13C NMR (125.7 MHz, MeOD) l 73.0
(C-4, C-5), 67.6 (C-3, C-6), and 47.9 (C-2, C-7).
HRCIMS calcd for C6H14NO4: 164.0923. Found
164.0924.
Acknowledgements
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica of Spain (grant numbers
PB97/0730 and BQU 2001-3740) and the Junta de
Andalucia (FQM-134) for financial support, and the
Ministerio de Educacio´n, Cultura y Deportes of Spain
for the award of a fellowship to F.J.S. This work is part
of the European Programme COST D13, action num-
ber D13/0001/98.
12. Fuentes, J.; Olano, D.; Pradera, M. A. Tetrahedron Lett.
1999, 40, 4063–4066.
13. Go´mez Sa´nchez, A.; Go´mez Guille´n, M.; Cert Ventula´,
A.; Scheidegger, U. An. Quim. 1968, 64B, 579–590.
14. Fuentes Mota, J.; Ferna´ndez-Bolan˜os Guzma´n, J.; Gar-
c´ıa Ferna´ndez, J. M.; Moreda, W.; Ortiz, C.; Pradera, M.
A.; Robina, I.; Welsh, C. Carbohydr. Res. 1992, 232,
47–57.

J. Fuentes et al. / Tetrahedron: Asymmetry 13 (2002) 1743–1753
1753
15. For NMR and MS data of related compounds with
D-gluco configuration, see: Fuentes, J.; Cuevas, T.;
Pradera, M. A. Tetrahedron 1993, 49, 6235–6250.
16. Grindly, T. B.; Thangarasa, R. Carbohydr. Res. 1988,
172, 311–318.
M. A. Tetrahedron: Asymmetry 2000, 11, 2471–2482.
19. For the numbering of the perhydroazepine derivatives
30–35 we have considered C-3 as a carbon atom having
R configuration. In the cases of compounds 32 and 35,
where both possible C-3 centres have (R)-configuration,
for homogeneity reasons, we have considered C-3 the
carbon coming from C-5 of the sugar ring (see Scheme
1).
20. Leeuwenburgh, M. A.; Picasso, S.; Overkleeft, H. S.;
van der Marel, G. A.; Vogel, P.; van Boom, J. H. Eur.
J. Org. Chem. 1999, 1185–1189.
17. Lafont, D.; Wollny, A.; Boullanger, P. Carbohydr. Res.
1998, 310, 9–16.
18. For the description of the N-deprotection method, see:
Go´mez Sa´nchez, A.; Borrachero Moya, P.; Bellanato, J.
Carbohydr. Res. 1984, 135, 101–116. For a recent appli-
cation, see: Fuentes, J.; Olano, D.; Gasch, C.; Pradera,