The first synthesis of substituted azepanes mimicking monosaccharides: A new class of potent glycosidase inhibitors

Article abstract of DOI:10.1039/b402542c

The synthesis of the first examples of seven-membered ring iminoalditols, molecules displaying an extra hydroxymethyl substituent on their seven-membered ring compared to the previously reported polyhydroxylated azepanes, has been achieved from D-arabinos

Full text of DOI:10.1039/b402542c

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The first synthesis of substituted azepanes mimicking
monosaccharides: a new class of potent glycosidase inhibitors
Hongqing Li,a Yves Blériot,*a Caroline Chantereau,a Jean-Maurice Mallet,a
Matthieu Sollogoub,a Yongmin Zhang,a Eliazar Rodríguez-García,b Pierre Vogel,b
Jesús Jiménez-Barberoc and Pierre Sinaÿ*a
a Ecole Normale Supérieure, Département de Chimie, UMR 8642, 24 rue Lhomond,
75231 Paris Cedex 05, France. E-mail: yves.bleriot@ens.fr; pierre.sinay@ens.fr
b Institut des Sciences et Ingéniérie Chimiques, Ecole Polytechnique Fédérale de Lausanne,
BCH, CH-1015 Lausanne, Switzerland
c Centro de Investigaciones Biologicas, CSIC, Ramiro De Maeztu 9, 28040 Madrid, Spain
Received 20th February 2004, Accepted 19th March 2004
First published as an Advance Article on the web 20th April 2004
The synthesis of the first examples of seven-membered ring iminoalditols, molecules displaying an extra
hydroxymethyl substituent on their seven-membered ring compared to the previously reported polyhydroxylated
azepanes, has been achieved from -arabinose in 10 steps using RCM of a protected N-allyl-aminohexenitol as a
key step. While the (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxy-azepane 10, a seven-membered ring analogue of
fagomine, is a weak inhibitor of glycosidases, the (2R,3R,4R,5S,6S)-2-hydroxymethyl-3,4,5,6-tetrahydroxy-azepane 9
selectively inhibits green coffee bean α-galactosidase in the low micromolar range (Ki = 2.2 µM) despite a -gluco
relative configuration.
carbohydrate mimetics in order to find more potent/selective
Introduction
glycosidase inhibitors.11
Glycosidase inhibitors have been the subject of extensive
interest in the past two decades due to their therapeutic
potential.1 Some of them have already been tested or approved
in the treatment of diabetes,2 Gaucher’s disease,3 HIV infec-
tion,4 viral infections5 or cancer.6 They have also been used as
chemical probes, in combination with protein crystallography
and kinetics studies, to provide new insight into glycosidase
mechanisms7 and are now expected to find an increasing
number of therapeutic applications.8
A common strategy for designing such inhibitors is based on
the mimicry of the cyclic alkoxycarbenium-like transition state
occurring during the glycosidic bond cleavage. For this purpose,
a large number of aminated compounds, wherein a nitrogen
atom has replaced the endocyclic oxygen or the anomeric
carbon of the parent sugar, have been synthesized.9 At physio-
logical pH, these aminated compounds are protonated and thus
develop a positive charge which provides stabilizing electro-
static interactions with active site carboxylate residues, and
might serve to mimic the charge present in the oxycarbenium-
like transition state in glycosidase-catalyzed hydrolysis reac-
tions. Many synthetic efforts have been devoted to the design of
substituted pyrrolidines and piperidines, which mimic the ring
size and the substitution pattern of the parent sugar, but
only a few syntheses of higher homologues, that is, substituted
azepanes and azocanes, have been reported so far. A very recent
paper by Martin and co-workers on the first synthesis of an
eight-membered ring iminoalditol10 prompted us to publish our
results describing the first synthesis of seven-membered ring
aminoalditols. This work is part of an ongoing project on new
Tri- and tetrahydroxylated azepanes were prepared for the
first time by Paulsen and Todt in 196712 and extensively studied
in the last decade.13 A selection of these synthetic substituted
azepanes is shown in Fig. 1.
Malto-oligosaccharides14 and analogues of di- and tri-
saccharides15 containing them have been also described. These
compounds are glycosidase13c,13d,13e,14,15 and/or HIV/FIV pro-
tease inhibitors.13d Some derivatives have exhibited anticancer
activities in various cancer lines with GI50 values in the low
micromolar range13c while others have been used as new motifs
for DNA minor groove binding agents.13f
To our knowledge, 1,6-dideoxy-1,6-iminoheptitols (see Fig. 2)
have not been described so far. Unlike all the polyhydroxylated
azepanes reported to date displaying only secondary hydroxyl
groups (see Fig. 1), the compounds described herein possess an
extra hydroxymethyl group which may allow an additional
favourable interaction of these molecules in the glycosidase
active site. They constitute a novel family of polyhydroxylated
azepanes and can be considered as higher homologues of
nojirimycin and fagomine (Fig. 2). Insertion of a methylene
group between the nitrogen atom and the pseudo-anomeric
hydroxyl group ensures chemical stability of these compounds
unlike nojirimycin. Such structures are more flexible than the
corresponding pyrrolidines and piperidines and should adopt
several puckered low-energy conformations.13d They should
thus be able to adapt to the space filling and polar requirements
of glycosidases. The subsequent unusual spatial distribution
of the hydroxyl groups present in these compounds should
hopefully generate a new inhibition profile for these molecules.
Fig. 1 Four examples of synthetic tetrahydroxylated azepanes.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 4 9 2 – 1 4 9 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Fig. 2 General structure of substituted azepanes synthesized in this work and comparison with the well known inhibitors nojirimycin and
fagomine.
Scheme 1 Synthesis of -arabino and -xylo aminohexenitols 2 and 3 from -arabinose. Conditions: i) Ref. 18 ii) allylamine, AcOH, NaBH3CN,
CH2Cl2, 30 ЊC, 58% yield.
Scheme 2 Synthesis of seven-membered iminoalditols 8–10. Conditions: i) ZCl, KHCO3, 91% yield; ii) Grubbs’ catalyst A, DCM, 45 ЊC, 3 days, 91%
yield; iii) OsO4, NMO, acetone/water, 96% yield; iv) H2, 10% Pd/C, AcOH, quant. yield.
Scheme 3 Synthesis of seven-membered iminoalditols 15–17. Conditions: i) ZCl, KHCO3, 90% yield; ii) Grubbs’ catalyst A, DCM, 45 ЊC, 3 days,
84% yield; iii) OsO4, NMO, acetone/water, 89% yield; iv) H2, 10% Pd/C, AcOH, quant. yield.
protected with a benzyloxycarbonyl group to afford carbamate
4 in 90% yield. Subsequent olefin metathesis of the diene 4
using Grubbs’catalyst proceeded in excellent yield to afford
Results and discussion
Synthesis
Our synthetic strategy, relying on the powerful ring-closing
alkene metathesis (RCM) methodology,16 is similar to the one
recently reported by Martin.10 Several other iminosugar-based
glycosidase inhibitors17 have also been obtained through RCM.
Reductive amination of the known ketone 1,18 easily available
from -arabinose, with allylamine and acetic acid in the
presence of NaBH3CN gave the -arabino and -xylo N-allyl-
aminohexenitols 2 and 3 in 58% yield (ratio 3 : 2) (Scheme 1).
In order to suppress the chelation of the ruthenium
catalyst by the amine moiety in the forthcoming RCM step,19
the secondary amine of the -arabino aminodiene 2 was
didehydroazepane 5 in 91% yield. Dihydroxylation of 5 (OsO4,
NMO) proceeded smoothly with modest facial diastereo-
selectivity to give cis diols 6 and 7 in 96% yield (3 : 7 ratio).
Hydrogenolysis of the benzyl ethers in 5–7 afforded the target
1,6-dideoxy-1,6-iminoheptitols 8–10 in quantitative yield
(Scheme 2).
The same sequence was uneventfully applied to the -xylo
N-allyl-aminohexenitol 3 to afford the 1,6-dideoxy-1,6-imino-
heptitols 15–17 (Scheme 3).
The pseudo β--manno, α--gluco, α--gulo and β--ido
configurations of compounds 8, 9, 15 and 16, respectively, were
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Table 1 Selected vicinal 3JH,H for compounds 8, 9, 15 and 16
Relative configuration
β--Manno
α--Gluco
α--Gulo
β--Ido
3JH,H
J1,2 = 1.4 Hz
J2,3 = 1.9 Hz
J3,4 = 8.8 Hz
J4,5 = 8.8 Hz
J1,2 = 2.4 Hz
J2,3 = 8.4 Hz
J3,4 = 8.4 Hz
J4,5 = 9.4 Hz
J1,2 = 2.0 Hz
J2,3 = 2.9 Hz
J3,4 = n.d.
J1,2 = 6.3 Hz
J2,3 = 6.3 Hz
J3,4 = 2.7 Hz
J4,5 ≈ 0 Hz
J4,5 = 1.0 Hz
Scheme 4 Synthesis of 1,6-dideoxy-1,6-iminoheptitol 16 via a different route. Conditions: i) Ref. 21; ii) 50% aq. TFA, quant. yield.
3
indicated by the vicinal JH,H coupling constants in their
epididymis A and B. For other enzymes the results are shown in
Table 2.
1H-NMR spectra (see Table 1).
Because of the relative conformational flexibility of seven-
Compound 9 shows the highest inhibitory activity toward
α-galactosidase from coffee beans (Ki = 2.2 µM, competitive)
and ignores other α-galactosidases and many other glyco-
sidases. Its 6-epimer 16 also inhibits α-galactosidase from coffee
beans (Ki = 16 µM, competitive). As both compounds 9 and
16 do not have the relative configuration of -galactopyranose,
it appears that they can adopt conformations imitating those
of α--galactose in the active site of the enzyme or bind in a
different way from their parent sugar in the binding pocket of
the hydrolase. The same hypotheses can be retained to explain
the good competitive inhibition (Ki = 5.7 µM) of β-galacto-
sidase from bovine liver by compound 8. This compound,
with the relative configuration of β--mannopyranose, is not
recognized by β-mannosidase from Helix pomatia, but by all
the glycosidases listed in Table 2. It is thus the least selective
inhibitor amongst the five seven-membered ring iminoalditols
assayed in this work. We can notice that these iminoheptitols
are more potent than the iminooctitol reported by Martin.10
This result can be explained by invoking the critical size of the
eight-membered ring. We need also to consider the lower degree
of hydroxylation and the different orientation of the OH
groups imposed by the specific conformation of the 1,2,3,7-
tetradeoxy-1,7-iminooctitol.
3
membered rings,20 the JH,H coupling constants are not fully
reliable to assess the configuration of the stereocentres in the
seven-membered ring iminoalditols. Fortunately, compound
16 was obtained using a different route (Scheme 4).21 The
known diol 1922 was converted into 16 via the semi-protected
precursor 18 from which the structure was unambiguously
established by X-ray crystallography (Fig. 3).23 Comparison
of the NMR data of stereoisomers 8, 9 and 15 with those of
16 confirmed our structural assignments (Table 1).
The lower degree of hydroxylation could also explain the
disappointing biological results obtained for compound 10,
a
seven-membered ring analogue of natural product
fagomine25(Fig. 1). Compound 10 was found to be a weak
inhibitor of amyloglucosidases and bovine liver α-galactosidase
and much less active than fagomine, reported to be a potent
α-glucosidase inhibitor.26
Fig. 3 X-ray structure of compound 18.
Conclusion
We have achieved for the first time the efficient preparation of
seven-membered ring iminoheptitols using RCM methodology
as the key step to afford new polyhydroxylated azepanes. Our
polyhydroxylated azepanes have an extra hydroxymethyl group
compared to the previously reported analogues.
Three of the six iminoalditols synthesized show potent
glycosidase inhibition in the low micromolar range, displaying a
new inhibition profile compared to the previously reported
polyhydroxylated azepanes. The best results are obtained with
compound 9, which is a selective and potent green coffee bean
Inhibitory activity
The new iminoheptitols 8, 9, 10, 15 and 16 have been assayed
for their inhibitory activity toward 24 commercially available
glycosidases.24 They did not inhibit the following enzymes at
1 mM concentration and optimal pH: α--fucosidase from
bovine epididymis, α-galactosidases from Aspergillus niger and
E. coli, α-mannosidases from Jack beans and from almonds,
β-mannosidase from Helix pomatia, β-xylosidase from A. niger,
β-N-acetylglucosaminidases from Jack beans and bovine
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 4 9 2 – 1 4 9 9
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α-galactosidase inhibitor. The inhibition profile observed for
each seven-membered ring iminoalditol, which can not be
correlated to its relative configuration, could be explained by a)
the relative flexibility of these iminoalditols adopting a specific
conformation in the binding pocket that favorably orientates
the hydroxyl groups in the enzyme active site and/or b) by the
different positioning of these compounds in the enzyme active
site compared to the corresponding parent sugar.
A conformational study of these molecules, as well as
docking experiments with model glycosidases, are under way
to determine their active conformation and hopefully better
understand their inhibition profile.
Experimental section
General methods
Melting points (mp) were determined with a Büchi B-535
apparatus and are uncorrected. Optical rotations were
measured at 20 2 ЊC with a Perkin Elmer Model 241 digital
polarimeter, using a 10 cm, 1 mL cell. Chemical Ionisation
Mass Spectra (CI-MS ammonia) and Fast Atom Bombardment
Mass Spectra (FAB-MS) were recorded on a JMS-700 spectro-
meter. Elemental analyses were performed by the Service de
Microanalyse de l’Université Pierre et Marie Curie, 4 Place
1
Jussieu, 75005 Paris, France. H NMR and 13C NMR were
performed on a Bruker DRX 400 spectrometer (400 MHz for
1H, 100.6 MHz for 13C). All chemical shifts (δ) are given in ppm
relative to the residual deuterated solvent signals. Coupling
constants (J) are reported in Hertz. Reactions were monitored
by thin-layer chromatography (TLC) using Merck silica gel 60
F254 precoated plates and detection by charring with sulfuric
acid. Flash column chromatography was performed on silica
gel 60 Merck 60 (230–400 mesh).
Note: for the assignment of the NMR spectra, the numbering
of all the cyclic compounds in this paper is based on the
analogy with the corresponding parent sugar, as shown in
Table 1, and not on the IUPAC rules for commodity reasons.
(3R,4R,5R)-5-Allylamino-3,4,6-tribenzyloxy-hex-1-ene 2 and
(3R,4R,5S )-5-allylamino-3,4,6-tribenzyloxy-hex-1-ene 3. To a
solution of ketone 1 (500 mg, 1.2 mmol) in dry CH2Cl2 (10 mL)
was added AcOH (0.21 mL), NaBH(OAc)3 (0.38 g, 1.79 mmol)
and allylamine (0.30 mL, 4 mmol) at RT under argon. The
reaction mixture was stirred for 36 hours at 40 ЊC and quenched
by 1 M aq. NaOH (4 mL) at RT. The reaction mixture was
extracted with CH2Cl2 (3 × 30 mL). The organic extracts were
dried with MgSO4, the solution was filtered and the solvent was
evaporated. Purification by flash chromatography (AcOEt/
cyclohexane, 1 : 6) afforded diene 3 (128 mg, 23% yield) as an oil.
1
[α]D ϩ14 (c = 1.01 in CHCl3); H NMR (CDCl3, 400 MHz):
7.38–7.30 (m, 15H, aromatic H), 5.94–5.82 (m, 2H, H-2, H-8),
5.41 (m, 1H, H-1a), 5.37 (m, 1H, H-1b), 5.16 (ddd, 1H, J = 1.6
Hz, J = 3.3 Hz, J = 17.1 Hz, H-9a), 5.06 (ddd, 1H, J = 1.4 Hz,
J = 2.8 Hz, J = 10.0 Hz, H-9b), 4.93 (d, 1H, J = 11.2 Hz, CHPh),
4.66 (d, 1H, J = 11.6 Hz, CHPh), 4.60 (d, 1H, J = 11.2 Hz,
CHPh), 4.47 (d, 1H, J = 12.0 Hz, CHPh), 4.43 (d, 1H, J = 12.0
Hz, CHPh), 4.42 (d, 1H, J = 11.6 Hz, CHPh), 4.25 (dd, 1H,
J = 7.0 Hz, J = 7.5 Hz, H-3), 3.77 (dd, 1H, J = 3.3 Hz, J = 7.0
Hz, H-4), 3.53 (dd, 1H, J = 5.0 Hz, J = 9.2 Hz, H-6a), 3.48 (dd,
1H, J = 7.3 Hz, J = 9.2 Hz, H-6b), 3.37 (ddt, 1H, J = 1.4 Hz,
J = 6.0 Hz, J = 12.6 Hz, H-7a), 3.20 (ddt, 1H, J = 1.4 Hz, J = 6.0
Hz, J = 13.7 Hz, H-7b), 2.98 (ddd, 1H, J = 3.3 Hz, J = 5.0 Hz,
J = 7.3 Hz, H-5) 13C NMR (CDCl3, 100 MHz): 138.98, 138.63,
138.28 (3 × Cipso), 137.50 (C-8), 135.70 (C-2), 128.41–127.35
(15 aromatic C), 118.69 (C-1), 115.44 (C-9), 82.80 (C-3), 81.40
(C-4), 75.15, 73.02, 70.70 (3 × CH2Ph), 69.53 (C-6), 56.83 (C-5),
50.53 (C-7); m/z (CI, NH3): 458 (M ϩ Hϩ, 100%); Anal. Calcd
for C30H35O3N: C, 78.74; H, 7.71; N, 3.06; Found C, 78.73; H,
7.77; N, 3.00%.
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Further elution afforded diene 2 (192 mg, 35% yield) as an
Hz, H-6a), 3.74 (dd, 1H, J = 8.2 Hz, J = 9.6 Hz, H-6Јb), 3.67
(dd, 1H, J = 7.6 Hz, J = 9.4 Hz, H-6b); 13C NMR (CDCl3, 100
oil.
1
[α]D Ϫ14 (c = 1.49 in CHCl3); H NMR (CDCl3, 400 MHz):
MHz): 155.85, 155.46 (2 × C᎐O), 138.47, 138.43, 138.38,
᎐
7.38–7.30 (m, 15H, aromatic H), 5.95 (ddd, 1H, J = 7.5 Hz,
J = 10.5 Hz, J = 18.1 Hz, H-2), 5.83 (m, 1H, H-8), 5.35 (m, 1H,
H-1a), 5.32 (m, 1H, H-1b), 5.14 (app. dq, 1H, J = 1.6 Hz,
J = 17.1 Hz, H-9a), 5.06 (app. dq, 1H, J = 1.4 Hz, J = 10.2 Hz,
H-9b), 4.81 (d, 1H, J = 11.4 Hz, CHPh), 4.68 (d, 1H, J = 11.4
Hz, CHPh), 4.67 (d, 1H, J = 11.8 Hz, CHPh), 4.57 (d, 1H,
J = 12.0 Hz, CHPh), 4.49 (d, 1H, J = 12.0 Hz, CHPh), 4.42
(d, 1H, J = 11.8 Hz, CHPh), 4.22 (dd, 1H, J = 4.8 Hz, J = 7.5
Hz, H-3), 3.69 (dd, 1H, J = 4.1 Hz, J = 9.6 Hz, H-6a), 3.65 (m,
2H, H-4, H-6b), 3.23 (ddt, 1H, J = 1.4 Hz, J = 6.2 Hz, J = 15.1
Hz, H-7a), 3.13 (ddt, 1H, J = 1.4 Hz, J = 5.6 Hz, J = 13.9 Hz,
H-7b), 3.03 (m, 1H, H-5); 13C NMR (CDCl3, 100 MHz):
138.76, 138.45, 138.38 (3 × Cipso), 137.29 (C-8), 136.02 (C-2),
128.27–127.38 (15 aromatic C), 118.27 (C-1), 115.43 (C-9),
81.37 (C-4), 81.10 (C-3), 74.73, 73.02, 70.51 (3 × CH2Ph), 68.50
(C-6), 57.35 (C-5), 50.20 (C-7); m/z (CI, NH3): 458 (M ϩ Hϩ,
100%); Anal. Calcd for C30H35O3N: C, 78.74; H, 7.71; N, 3.06;
Found C, 78.79; H, 7.85; N, 2.89%.
138.29, 138.21, 138.10 (6 × Cipso), 136.89, 136.73 (2 × Cipso),
133.49, 132.14 (C-1, C-1Ј), 128.40–127.43 (20 aromatic C),
127.21, 126.31 (C-2, C-2Ј), 78.99, 78.86 (C-4, C-4Ј), 75.93, 75.69
(C-3, C-3Ј), 73.09, 73.01, 72.91, 71.80, 71.63, 67.27, 67.10 (8 ×
CH2Ph), 66.52, 65.97 (C-6, C-6Ј), 54.59, 54.24 (C-5, C-5Ј),
42.67, 42.15 (C-7, C-7Ј); m/z (CI, NH3): 564 (M ϩ Hϩ, 100%),
ϩ
581 (M ϩ NH4 , 55%); Anal. Calcd for C36H37O5N: C, 76.71;
H, 6.62; N, 2.48; Found C, 76.74; H, 6.59; N, 2.48%.
(2R,3R,4R,5R,6R)-N-Benzyloxycarbonyl-2-benzyloxy-
methyl-3,4-dibenzyloxy-5,6-dihydroxy-azepane
6
and
(2R,3R,4R,5S,6S )-N-benzyloxycarbonyl-2-benzyloxymethyl-
3,4-dibenzyloxy-5,6-dihydroxy-azepane 7. Compound 5 (130
mg, 0.231 mmol) was dissolved in acetone/water (8 : 1, 1 mL).
NMO (110 mg, 0.94 mmol) was added, followed by OsO4
(0.05 mL, 2.5% wt in t-BuOH). The reaction mixture was
stirred for 24 hours at 30 ЊC and then quenched by addition
of Na2S2O3.5H2O (28 mg, 0.112 mmol). The reaction mixture
was then saturated with NaCl, extracted thoroughly with
CH2Cl2 (2 × 20 mL). The organic layer was dried with MgSO4
and concentrated to give a residue that was purified by flash
chromatography (AcOEt/cyclohexane, 2 : 3) to afford diol 6
(40 mg, 0.067 mmol, 28% yield).
(3R,4R,5R)-N-Benzyloxycarbonyl-5-allylamino-3,4,6-tri-
benzyloxy-hex-1-ene 4. Benzyl chloroformate (0.06 mL, 0.43
mmol) was added dropwise over a period of 30 min to an
ice-cold solution of diene 2 (93 mg, 0.204 mmol) and KHCO3
(0.38 g, 3.8 mmol) in a H2O/AcOEt mixture (10 mL, 1 : 1, v/v).
The reaction mixture was stirred for 6 hours at RT, the organic
layer was separated, washed with 1 M aq. HCl (5 mL) and brine
(5 mL), dried with MgSO4, filtered and the solvent was
evaporated. Purification by flash chromatography (AcOEt/
cyclohexane, 1 : 8) afforded carbamate 4 (110 mg, 91% yield) as
an oil.
1
[α]D Ϫ10 (c = 1.08 in CHCl3); H NMR (CDCl3, 400 MHz):
7.39–7.23 (m, 40H, aromatic H), 5.17 (s, 2H, CH2Ph), 5.16 (d,
1H, J = 12.3 Hz, CHPh), 5.10 (d, 1H, J = 12.3 Hz, CHPh), 4.89
(d, 1H, J = 10.9 Hz, CHPh), 4.88 (d, 1H, J = 11.2 Hz, CHPh),
4.83 (d, 2H, J = 11.3 Hz, 2 × CHPh), 4.65 (d, 1H, J = 11.6 Hz,
CHPh), 4.60 (d, 1H, J = 11.3 Hz, CHPh), 4.52 (d, 1H, J = 11.2
Hz, CHPh), 4.52 (d, 1H, J = 10.9 Hz, CHPh), 4.47 (d, 1H,
J = 12.2 Hz, CHPh), 4.46 (d, 1H, J = 10.9 Hz, CHPh), 4.40 (d,
1H, J = 12.1 Hz, CHPh), 4.38 (d, 1H, J = 12.2 Hz, CHPh), 4.28–
4.23 (m, 3H, H-4, H-4Ј, H-5Ј), 4.23–4.20 (m, 3H, H-2, H-2Ј,
H-3Ј), 4.15 (m, 1H, H-5), 3.83–3.66 (m, 6H, H-1, H-3, H-6a,
H-6Јa, H-7a, H-7Јa), 3.65 (dd, 1H, H-6Јb), 3.61 (m, 1H, H-1),
3.55 (dd, 1H, H-6b), 3.37 (dd, 1H, H-7Јb), 3.29 (dd, 1H, H-7b);
13C NMR (CDCl , 100 MHz): 156.07, 155.90 (2 × C᎐O),
1
[α]D ϩ 4 (c = 1.31 in CHCl3); H NMR (CDCl3, 400 MHz,
2 rotamers): 7.41–7.30 (m, 40H, aromatic H), 6.02–5.78 (m, 4H,
H-2, H-2Ј, H-8, H-8Ј), 5.40–5.01 (m, 8H, H-1, H-1Ј, H-9, H-9Ј,
H-6a, H-6b, H-6Јa, H-6Јb), 4.85 (m, 2H, 2 × CHPh), 4.65–4.33
(m, 8H, 4 × CH2Ph), 4.09–3.68 (m, 8H, H-3, H-4, H-5, H-7a,
H-7b, H-7Јa, H-7Јb); 13C NMR (CDCl3, 100 MHz): 156.08
(C᎐O), 138.33, 138.25, 138.11, 136.81 (4 × Cipso), 135.81,
᎐
᎐
3
135.41 (C-2, C-8), 128.31–127.35 (20 aromatic C), 119.13,
119.01 (C-1, C-1Ј), 115.68, 115.42 (C-9, C-9Ј), 81.91, 81.59,
81.20 (C-3, C-4, C-5), 74.71, 72.68, 70.43 (4 × CH2Ph), 68.20,
67.93, 67.18, 66.87 (C-6, C-6Ј, C-7, C-7Ј); m/z (CI, NH3): 592
138.14, 138.02, 137.98, 137.93, 137.85 (6 × Cipso), 136.40,
136.23 (2 × Cipso), 128.51–127.47 (20 aromatic C), 82.51,
81.81, 72.76, 72.67, 71.92, 71.78, 69.70, 68.58 (C-1, C-2, C-3, C-
4, C-1Ј, C-2Ј, C-3Ј, C-4Ј), 74.74, 74.36, 74.05, 72.92, 72.89,
67.56, 67.32 (8 × CH2Ph), 69.42, 69.19 (C-6, C-6Ј), 58.67, 58.59
(C-5, C-5Ј), 45.07, 44.48 (C-7, C-7Ј); m/z (CI, NH3): 598
ϩ
(M ϩ Hϩ, 82%), 609 (M ϩ NH4 , 100%); Anal. Calcd for
C38H41O5N: C, 77.13; H, 6.98; N, 2.37; Found C, 77.25; H, 7.04;
N, 2.20%.
ϩ
(M ϩ Hϩ, 55%), 615 (M ϩ NH4 , 100%); HRMS (CI, NH3):
Calcd for C36H40O7N (M ϩ Hϩ): 598.2805, Found 598.2800.
Further elution afforded diol 7 (94 mg, 0.157 mmol, 68%
yield).
(2R,3R,4R)-N-Benzyloxycarbonyl-2-benzyloxymethyl-3,4-
dibenzyloxy-5,6-didehydro-azepane 5. Compound 4 (106 mg,
0.179 mmol) was dissolved in dry CH2Cl2 (50 mL) and the
solution was degassed for 30 min by bubbling argon through
the solution. Grubbs’ catalyst (16 mg, 0.019 mmol, 10%mol)
was added and the solution was stirred for 76 hours at 45 ЊC
under argon. The reaction was quenched by stirring the reac-
tion mixture with Pb(OAc)4 (16 mg, 0.036 mmol) for 5 hours.
The solvent was evaporated and the residue purified by flash
1
[α]D ϩ 4 (c = 1.02 in CHCl3); H NMR (CDCl3, 400 MHz,
2 rotamers): 7.39–7.26 (m, 40H, aromatic H), 5.24 (d, 1H,
J = 12.3 Hz, CHPh), 5.22 (d, 1H, J = 12.5 Hz, CHPh), 5.18 (d,
1H, J = 12.5 Hz, CHPh), 5.16 (d, 1H, J = 12.3 Hz, CHPh), 5.06
(d, 1H, J = 11.1 Hz, CHPh), 5.04 (d, 1H, J = 11.1 Hz, CHPh),
4.98 (d, 1H, J = 10.9 Hz, CHPh), 4.96 (d, 1H, J = 11.2 Hz,
CHPh), 4.64 (d, 1H, J = 11.1 Hz, CHPh), 4.58 (d, 1H, J = 11.2
Hz, CHPh), 4.53 (d, 1H, J = 11.2 Hz, CHPh), 4.48 (d, 1H,
J = 12.0 Hz, CHPh), 4.47 (d, 1H, J = 10.9 Hz, CHPh), 4.43 (d,
1H, J = 11.7 Hz, CHPh), 4.38 (dd, 1H, J = 4.8 Hz, J = 15.9 Hz,
H-7a), 4.36 (d, 1H, J = 10.7 Hz, CHPh), 4.35 (m, 1H, H-5Ј),
4.33 (d, 1H, J = 12.0 Hz, CHPh), 4.25 (dd, 1H, J = 5.1 Hz,
J = 15.7 Hz, H-7Јa), 4.13 (app. t, 1H, J = 4.1 Hz, H-1), 4.09 (dt,
1H, J = 2.1 Hz, J = 2.4 Hz, J = 9.2 Hz, H-5), 4.01 (app. t, 1H,
J = 4.0 Hz, H-1Ј), 3.83 (dd, 1H, J = 2.9 Hz, J = 9.8 Hz, H-6a),
3.86–3.73 (m, 5H, H-3, H-3Ј, H-4, H-4Ј, H-6Јa), 3.68 (dd, 1H,
J = 2.6 Hz, J = 9.8 Hz, H-6b), 3.62–3.55 (m, 3H, H-2, H-2Ј,
H-6Јb), 3.31 (d, 1H, J = 16.4 Hz, H-7b), 3.27 (dd, 1H, J = 15.7
Hz, H-7Јb); 13C NMR (CDCl3, 100 MHz): 157.91, 156.78
chromatography (AcOEt/cyclohexane,
1 : 8) to afford
compound 5 (92 mg, 91% yield) as an oil.
1
[α]D Ϫ67 (c = 0.9 in CHCl3); H NMR (CDCl3, 400 MHz,
2 rotamers): 7.37–7.25 (m, 40H, aromatic H), 6.06 (ddd, 1H,
J = 2.1 Hz, J = 6.1 Hz, J = 11.5 Hz, H-1), 5.92 (ddd, 1H, J = 2.2
Hz, J = 6.1 Hz, J = 11.7 Hz, H-1Ј), 5.77 (m, 2H, H-2, H-2Ј),
5.18 (s, 2H, CH2Ph), 5.14 (d, 1H, J = 12.4 Hz, CHPh), 5.02 (d,
1H, J = 12.4 Hz, CHPh), 5.01 (m, 1H, H-5Ј), 4.86 (m, 1H, H-5),
4.65–4.50 (m, 12H, 6 × CH2Ph), 4.40 (m, 1H, H-7a), 4.30 (m,
1H, H-7Јa), 4.27 (m, 1H, H-3), 4.23 (m, 1H, H-3Ј), 4.08 (dd,
1H, J = 4.3 Hz, J = 6.9 Hz, H-4Ј), 4.05 (dd, 1H, J = 4.4 Hz,
J = 6.8 Hz, H-4), 3.90–3.80 (m, 2H, H-7b, H-7Јb), 3.87 (dd, 1H,
J = 7.0 Hz, J = 9.6 Hz, H-6Јa), 3.83 (dd, 1H, J = 7.3 Hz, J = 9.4
(2 × C᎐O), 138.10, 137.94, 137.91, 137.89, 137.84, 137.73
᎐
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 4 9 2 – 1 4 9 9
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(6 × Cipso), 136.69, 136.22 (2 × Cipso), 128.49–127.57 (20
aromatic C), 80.59, 80.17, 78.06, 77.84 (C-3, C-3Ј, C-4, C-4Ј),
76.06, 75.76, 75.60, 74.24, 73.20, 73.09, 67.90, 67.41 (8 ×
CH2Ph), 75.55, 75.01 (C-2, C-2Ј), 69.92, 69.57 (C-6, C-6Ј),
67.97, 67.39 (C-1, C-1Ј), 58.09, 57.94 (C-5, C-5Ј), 44.70, 44.41
(C-7, C-7Ј); m/z (CI, NH3): 490 (100%), 507 (50%), 598
CH2Ph), 68.52, 68.26, 66.99 (C-6, C-6Ј, C-7, C-7Ј); m/z (CI,
ϩ
NH3): 592 (M ϩ Hϩ, 72%), 609 (M ϩ NH4 , 100%); Anal.
Calcd for C38H41O5N: C, 77.13; H, 6.98; N, 2.37; Found C,
77.11; H, 7.17; N, 2.23%.
(2S,3R,4R)-N-Benzyloxycarbonyl-2-benzyloxymethyl-3,4-
dibenzyloxy-5,6-didehydro-azepane 12. This product was
synthesized as previously described for compound 5.
Carbamate 11 (90 mg, 0.152 mmol) afforded compound 12
(72 mg, 84% yield) as an oil.
ϩ
(M ϩ Hϩ, 4%), 615 (M ϩ NH4 , 2%); HRMS (CI, NH3): Calcd
for C36H40O7N (M ϩ Hϩ): 598.2805, Found 598.2814.
(2R,3R,4R,5R,6R)-2-Hydroxymethyl-3,4,5,6-tetrahydroxy-
azepane 8. Diol 6 (87 mg, 0.145 mmol) was dissolved in AcOH
(6.5 mL) and 10% Pd/C (10 mg) was added. The suspension was
stirred under H2 for 4 hours at 30 ЊC, filtered through Celite and
eluted with MeOH. The solvent was removed under reduced
pressure to afford compound 8 as a colorless oil (28 mg, 0.145
mmol, quant. yield).
1
[α]D Ϫ14 (c = 0.79 in CHCl3); H NMR (CDCl3, 400 MHz):
7.38–7.25 (m, 40H, aromatic H), 5.79–5.68 (m, 4H, H-1, H-1Ј,
H-2, H-2Ј), 5.17 (m, 4H, 2 × CH2Ph), 4.98 (d, 1H, J = 11.3 Hz,
CHPh), 4.95 (d, 1H, J = 11.1 Hz, CHPh), 4.82 (d, 1H, J = 11.6
Hz, CHPh), 4.75 (d, 1H, J = 11.7 Hz, CHPh), 4.70 (d, 1H,
J = 11.6 Hz, CHPh), 4.68 (d, 1H, J = 11.7 Hz, CHPh), 4.60 (m,
1H, H-5), 4.54 (d, 1H, J = 11.3 Hz, CHPh), 4.51 (d, 1H, J = 11.1
Hz, CHPh), 4.50 (d, 1H, J = 12.0 Hz, CHPh), 4.49 (d, 1H,
J = 12.0 Hz, CHPh), 4.47 (m, 1H, H-5Ј), 4.34–4.26 (m, 4H, H-3,
H-3Ј, H-7a, H-7Јa), 3.92–3.73 (m, 6H, H-4, H-4Ј, H-6a, H-6Јa,
H-7b, H-7Јb), 3.65 (dd, 1H, J = 2.9 Hz, J = 10.2 Hz, H-6Јb),
3.58 (dd, 1H, J = 3.2 Hz, J = 10.2 Hz, H-6b); 13C NMR (CDCl3,
1
[α]D Ϫ9 (c = 1.07 in CH3OH); H NMR (D2O, 400 MHz):
4.22 (ddd, 1H, J = 1.4 Hz, J = 5.9 Hz, J = 8.7 Hz, H-1), 4.15 (dd,
1H, J = 1.4 Hz, J = 1.9 Hz, H-2), 3.96 (dd, 1H, J = 3.8 Hz,
J = 12.3 Hz, H-6a), 3.85 (app. t, 1H, J = 8.8 Hz, H-4), 3.76 (dd,
1H, J = 7.2 Hz, J = 12.3 Hz, H-6b), 3.74 (dd, 1H, J = 1.9 Hz,
J = 8.8 Hz, H-3), 3.41 (dd, 1H, J = 5.8 Hz, J = 13.5 Hz, H-7a),
3.27 (dd, 1H, J = 7.5 Hz, J = 13.5 Hz, H-7b), 3.24 (ddd, 1H,
J = 3.8 Hz, J = 7.2 Hz, J = 8.8 Hz, H-5); 13C NMR (D2O, 100
MHz): 75.25 (C-3), 74.78 (C-2), 68.67 (C-4), 66.18 (C-1), 60.84
(C-5), 59.67 (C-6), 47.06 (C-7); m/z (CI, NH3): 194 (M ϩ Hϩ,
100%); HRMS (CI, NH3): Calcd for C7H16O5N (M ϩ Hϩ):
194.1028, Found 194.1031.
100 MHz): 156.13, 156.03 (2 × C᎐O), 138.54, 138.44, 138.41,
᎐
138.24, 138.10, 137.95 (6 × Cipso), 136.69, 136.55 (2 × Cipso),
131.82, 131.26 (C-1, C-1Ј or C-2, C-2Ј), 128.77–127.53 (20
aromatic C), 128.40, 128.33 (C-1, C-1Ј or C-2, C-2Ј), 80.39,
80.10, 79.92 (C-3, C-4, C-5), 74.83, 74.66, 73.74, 73.40, 72.88,
72.80, 67.47, 67.28 (8 × CH2Ph), 69.31 (C-6, C-6Ј), 57.96, 57.55
(C-5, C-5Ј), 42.91 (C-7, C-7Ј); m/z (CI, NH3): 564 (M ϩ Hϩ,
ϩ
(2R,3R,4R,5S,6S )-2-Hydroxymethyl-3,4,5,6-tetrahydroxy-
azepane 9. Diol 7 (280 mg, 0.469 mmol) was deprotected as
described for compound 8 to afford compound 9 (90 mg, quant.
yield) as a colorless oil.
100%), 581 (M ϩ NH4 , 55%); Anal. Calcd for C36H37O5N: C,
76.71; H, 6.62; N, 2.48; Found C, 76.73; H, 6.61; N, 2.40%.
(2S,3R,4R,5R,6R)-N-Benzyloxycarbonyl-2-benzyloxymethyl-
3,4-dibenzyloxy-5,6-dihydroxy-azepane 13 and (2S,3R,4R,-
5S,6S )-N-benzyloxycarbonyl-2-benzyloxymethyl-3,4-dibenzyl-
oxy-5,6-dihydroxy-azepane 14. These products were syn-
thesized as previously described for compounds 6 and 7.
Compound 12 (69 mg, 0.122 mmol) afforded compounds 13
and 14 (64 mg, 0.107 mmol, 87% yield) in a 4 : 1 ratio and as
oils.
1
[α]D ϩ32 (c = 1.13 in CH3OH); H NMR (D2O, 400 MHz):
4.23 (ddd, 1H, J = 2.3 Hz, J = 2.4 Hz, J = 6.3 Hz, H-1), 3.94 (dd,
1H, J = 3.6 Hz, J = 12.5 Hz, H-6a), 3.85 (dd, 1H, J = 6.6 Hz,
J = 12.5 Hz, H-6b), 3.73 (app. t, 1H, J = 8.4 Hz, H-3), 3.65 (dd,
1H, J = 2.4 Hz, J = 8.4 Hz, H-2), 3.63 (dd, 1H, J = 8.4 Hz,
J = 9.4 Hz, H-4), 3.48 (ddd, 1H, J = 3.6 Hz, J = 6.6 Hz, J = 9.4
Hz, H-5), 3.36 (dd, 1H, J = 6.3 Hz, J = 14.2 Hz, H-7a), 3.28 (dd,
1H, J = 2.3 Hz, J = 14.2 Hz, H-7b); 13C NMR (D2O, 100 MHz):
74.38 (C-2), 73.47 (C-3), 68.62 (C-4), 66.33 (C-1), 59.19 (C-6),
59.17 (C-5), 44.45 (C-7); m/z (CI, NH3): 194 (M ϩ Hϩ, 100%);
HRMS (CI, NH3): Calcd for C7H16O5N (M ϩ Hϩ): 194.1028,
Found 194.1031.
Diol 13: [α]D ϩ12 (c = 1.1 in CHCl3); 1H NMR (CDCl3, 400
MHz): 7.37–7.24 (m, 40H, aromatic H), 5.22 (d, 1H, J = 12.4
Hz, CHPh), 5.17 (d, 1H, J = 12.4 Hz, CHPh), 5.16 (d, 1H,
J = 12.3 Hz, CHPh), 5.08 (d, 1H, J = 12.3 Hz, CHPh), 4.75 (m,
1H, J = 4.6 Hz, H-5), 4.66–4.50 (m, 9H, 4 × CH2Ph, H-5Ј), 4.46
(d, 1H, J = 12.0 Hz, CHPh), 4.41 (d, 1H, J = 12.0 Hz, CHPh),
4.27 (m, 1H, H-7a), 4.19 (m, 1H, H-7Јa), 4.18 (dd, 1H, J = 5.2
Hz, J = 7.4 Hz, H-4), 4.14 (m, 2H, H-3, H-3Ј), 4.11 (dd, 1H,
J = 5.1 Hz, J = 7.4 Hz, H-4Ј), 4.03 (m, 3H, H-1, H-2, H-2Ј), 3.93
(m, 1H, H-1Ј), 3.79 (dd, 1H, J = 8.7 Hz, J = 9.7 Hz, H-6Јa), 3.73
(dd, 1H, J = 8.9 Hz, J = 9.5 Hz, H-6a), 3.64 (dd, 1H, J = 5.0 Hz,
J = 8.7 Hz, H-6Јb), 3.50 (dd, 1H, J = 5.3 Hz, J = 8.9 Hz, H-6b),
3.35–3.28 (m, 3H, H-7b, H-7Јb, OH), 2.81 (d, 1H, J = 11.4 Hz,
OH); 13C NMR (CDCl3, 100 MHz): 157.53, 156.31 (2 × C=0),
138.21, 137.97, 137.60, 137.45, 137.15, 136.66, 136.35 (8 ×
Cipso), 128.61–127.47 (40 aromatic C), 82.62, 82.52 (C-3, C-3Ј),
74.89, 74.75, 74.21, 74.07 (4 × CH2Ph), 74.18, 73.89 (C-4, C-4Ј),
73.08, 73.05 (2 × CH2Ph), 72.44, 72.41 (C-1, C-1Ј), 69.86, 69.63
(C-2, C-2Ј), 67.71, 67.29 (2 × CH2Ph), 67.27, 66.67 (C-6, C-6Ј),
55.41 (C-5, C-5Ј), 44.17, 44.09 (C-7, C-7Ј); m/z (CI, NH3): 598
(2R,3R,4R)-2-Hydroxymethyl-3,4-dihydroxy-azepane
10.
Didehydro-azepane 5 (57 mg, 0.101 mmol) was deprotected as
described for compound 8 to afford compound 10 (16 mg,
quant. yield) as a colorless oil.
1
[α]D ϩ6.5 (c = 1.05 in CH3OH); H NMR (D2O, 400 MHz):
3.97 (dd, 1H, J = 3.6 Hz, J = 12.3 Hz, H-6a), 3.86 (dd, 1H,
J = 6.7 Hz, J = 12.3 Hz, H-6b), 3.78 (dt, 1H, J = 2.8 Hz, J = 8.4
Hz, H-3), 3.67 (app. t, 1H, J = 8.3 Hz, H-4), 3.28–3.40 (m, 2H,
H-7a, H-5), 3.18 (m, 1H, H-7b), 1.66–2.12 (m, 4H, H-1a, H-1b,
H-2a, H-2b); 13C NMR (D2O, 100 MHz): 73.95 (C-3), 72.18
(C-4), 60.52 (C-5), 59.75 (C-6), 46.13 (C-7), 28.53 (C-2), 19.16
(C-1); m/z (CI, NH3): 162 (M ϩ Hϩ, 100%); HRMS (CI, NH3):
Calcd for C7H16O3N (M ϩ Hϩ): 162.1130, Found 162.1125.
ϩ
(3R,4R,5S )-N-Benzyloxycarbonyl-5-allylamino-3,4,6-tri-
benzyloxy-hex-1-ene 11. This product was synthesized as
previously described for compound 4.
(M ϩ Hϩ, 100%), 615 (M ϩ NH4 , 30%); HRMS (CI, NH3):
Calcd for C36H40O7N (M ϩ Hϩ): 598.2805, Found 598.2797.
Diol 14: [α]D ϩ4 (c = 1.05 in CHCl3); 1H NMR (CDCl3, 400
MHz): 7.40–7.27 (m, 40H, aromatic H), 5.27 (d, 1H, J = 12.5
Hz, CHPh), 5.21 (d, 1H, J = 12.5 Hz, CHPh), 5.17 (d, 1H,
J = 12.4 Hz, CHPh), 5.13 (d, 1H, J = 12.4 Hz, CHPh), 4.74
(m, 1H, H-5), 4.74 (d, 2H, J = 10.5 Hz, 2 × CHPh), 4.69 (d, 1H,
J = 8.6 Hz, CHPh), 4.66–4.48 (m, 7H, 3 × CH2Ph, H-5Ј), 4.38
(app. t, 1H, J = 6.2 Hz, H-4), 4.30 (app. t, 1H, J = 6.1 Hz, H-4Ј),
4.18 (d, 1H, J = 8.8 Hz, H-2), 4.09–4.01 (m, 4H, H-1Ј, H-2Ј,
Diene 3 (100 mg, 0.219 mmol) afforded compound 11 (118
mg, 0.199 mmol, 90% yield) as an oil.
[α]D Ϫ23 (c = 1.06 in CHCl3); 13C NMR (CDCl3, 100 MHz):
156.31 (C᎐O), 138.72, 138.31, 138.23, 136.82 (4 × Cipso),
᎐
135.79, 135.48, 134.93, 134.67 (C-2, C-2Ј, C-8, C-8Ј), 128.33–
127.45 (20 aromatic C), 118.85, 118.70 (C-1, C-1Ј), 116.00 (C-9,
C-9Ј), 81.38, 80.86 (C-3, C-4, C-5), 75.25, 72.79, 70.56 (4 ×
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 4 9 2 – 1 4 9 9
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H-3, H-3Ј), 3.93 (m, 2H, H-1, H-7Јa), 3.88–3.78 (m, 3H, H-6a,
H-6Јa, H-7a), 3.71 (dd, 1H, J = 5.5 Hz, J = 9.0 Hz, H-6b), 3.62
(dd, 1H, J = 5.6 Hz, J = 9.1 Hz, H-6Јb), 3.32–3.22 (m, 2H, H-7b,
H-7Јb), 2.98 (d, 1H, J = 8.8 Hz, OH), 2.96 (d, 1H, J = 8.8 Hz,
OH); 13C NMR (CDCl3, 100 MHz): 155.62, 155.51 (2 × C=0),
137.85, 137.68, 137.46, 137.42, 136.59, 136.53, 136.26, 136.24
(8 × Cipso), 128.67–127.38 (40 aromatic C), 78.61, 78.54 (C-4,
C-4Ј), 75.40, 75.32 (2 × CH2Ph), 74.56, 73.94 (C-3, C-3Ј), 73.19,
73.10, 72.80, 72.73 (4 × CH2Ph), 72.62, 72.57 (C-2, C-2Ј), 69.52,
68.86 (C-1, C-1Ј), 67.25, 67.14 (2 × CH2Ph), 67.03, 66.74 (C-6,
C-6Ј), 53.92, 53.79 (C-5, C-5Ј), 44.66, 44.38 (C-7, C-7Ј); m/z
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ϩ
(CI, NH3): 598 (M ϩ Hϩ, 100%), 615 (M ϩ NH4 , 65%);
HRMS (CI, NH3): Calcd for C36H40O7N (M ϩ Hϩ): 598.2805,
Found 598.2800.
(2S,3R,4R,5R,6R)-2-Hydroxymethyl-3,4,5,6-tetrahydroxy-
azepane 15. Diol 13 (30 mg, 0.05 mmol) was deprotected as
described for compound 8 to afford compound 15 (10 mg, 0.05
mmol) as a colorless oil.
1
[α]D Ϫ5 (c = 0.95 in CH3OH); H NMR (D2O, 400 MHz):
4.28 (ddd, 1H, J = 2.0 Hz, J = 4.3 Hz, J = 8.7 Hz, H-1), 4.06 (dd,
1H, J = 2.0 Hz, J = 2.9 Hz, H-2), 4.02 (m, 2H, H-3, H-4), 3.91
(ddd, 1H, J = 1.0 Hz, J = 4.8 Hz, J = 9.1 Hz, H-5), 3.82 (dd, 1H,
J = 4.8 Hz, J = 11.9 Hz, H-6a), 3.74 (dd, 1H, J = 9.1 Hz, J = 11.9
Hz, H-6b), 3.36 (m, 2H, H-7a, H-7b); 13C NMR (D2O, 100
MHz): 73.60 (C-3), 72.52 (C-2), 69.45 (C-4), 68.88 (C-1), 60.78
(C-6), 57.84 (C-5), 45.92 (C-7); m/z (CI, NH3): 194 (M ϩ Hϩ,
100%); HRMS (CI, NH3): Calcd for C7H16O5N (M ϩ Hϩ):
194.1028, Found 194.1033.
(2S,3R,4R,5S,6S )-2-Hydroxymethyl-3,4,5,6-tetrahydroxy-
azepane 16. Diol 14 (120 mg, 0.20 mmol) was deprotected as
described for compound 8 to afford compound 16 (39 mg, 0.20
mmol) as a colorless oil.
7 T. D. Heightman and A. T. Vasella, Angew. Chem., Int. Ed., 1999, 38,
750–770; A. Vasella, G. J. Davies and M. Böhm, Curr. Opin. Chem.
Biol., 2002, 6, 619–629.
1
[α]D ϩ8 (c = 1.07 in CH3OH); H NMR (D2O, 400 MHz):
8 J. Alper, Science, 2001, 291, 2338–2343.
4.22 (br d, 1H, J = 6.5 Hz, H-1), 3.92 (dd, 1H, J = 2.7 Hz, J = 6.3
Hz, H-3), 3.87 (app. d, 1H, J = 6.3 Hz, H-2), 3.84 (d, 1H, J = 2.7
Hz, H-4), 3.74 (dd, 1H, J = 5.6 Hz, J = 11.9 Hz, H-6a), 3.67 (dd,
1H, J = 8.9 Hz, J = 11.9 Hz, H-6b), 3.48 (dd, 1H, J = 5.6 Hz,
J = 8.9 Hz, H-5), 3.46 (dd, 1H, J = 6.5 Hz, J = 13.8 Hz, H-7a),
3.25 (dd, 1H, J = 2.5 Hz, J = 13.8 Hz, H-7b); 13C NMR (D2O,
100 MHz): 76.84 (C-2), 74.49 (C-3), 70.05 (C-4), 68.25 (C-1),
60.68 (C-6), 58.31 (C-5), 47.97 (C-7); m/z (CI, NH3) : 194
(M ϩ Hϩ, 100%); HRMS (CI, NH3): Calcd for C7H16O5N
(M ϩ Hϩ): 194.1028, Found 194.1032.
9 A. Stütz, Iminosugars as glycosidase inhibitors: Nojirimycin and
Beyond, Wiley-VCH, Weinheim, 1999.
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(2S,3R,4R)-2-Hydroxymethyl-3,4-dihydroxy-azepane
17.
Didehydro-azepane 12 (49 mg, 0.087 mmol) was deprotected as
described for compound 8 to afford compound 17 (14 mg,
quant. yield) as a colorless oil.
1
[α]D Ϫ3.5 (c = 1.05 in CH3OH); H NMR (D2O, 400 MHz):
4.00 (m, 1H, H-3), 3.89 (d, 1H, J = 4.0 Hz, H-4), 3.81 (dd, 1H,
J = 5.4 Hz, J = 11.7 Hz, H-6a), 3.75 (dd, 1H, J = 8.7 Hz, J = 11.7
Hz, H-6b), 3.64 (m, 1H, H-5), 3.31–3.26 (m, 2H, H-7a, H-7b),
2.25–1.76 (m, 4H, H-1a, H-1b, H-2a, H-2b); 13C NMR (D2O,
100 MHz): 70.15 (C-3), 70.02 (C-4), 60.96 (C-6), 55.95 (C-5),
46.75 (C-7), 29.10 (C-2), 17.57 (C-1); m/z (CI, NH3): 162
(M ϩ Hϩ, 100%); HRMS (CI, NH3): Calcd for C7H16O3N (M ϩ
Hϩ): 162.1130, Found 162.1133.
Acknowledgements
We would like to thank the European Community’s Human
Potential Programme under contract HPRN-CT-2002-00173
for financial support and C. Guyard-Duhayon from the Centre
de Résolution des Structures (Université Pierre et Marie Curie),
for solving the X-Ray structure of compound 18. We thank also
the Swiss National Science Foundation and the Office Fédéral
de l’Education et de la Science (OFES, Bern) (COST D13) for
financial support.
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View Article Online
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23 Selected crystal structure data for 18; crystal system monoclinic;
space group P 21; Z = 2; cell parameters: a = 7.575(5), b = 13.478(6),
c = 10.641(11), α = 90, β = 109.04(5), γ = 90; radiation (Mo Kα)
λ = 0.710730 Å; 209 variables for 2106 reflections; final R = 0.0577,
RW
= 0.0680. CCDC reference number 228667. See http://
www.rsc.org/suppdata/ob/b4/b402542c/ for crystallographic data
in.cif or other electronic format.
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 4 9 2 – 1 4 9 9
1499