Design, synthesis and biological activity of azasugar-based CD163 ectodomain shedding inhibitors

Article abstract of DOI:10.1002/ejoc.200700178

A series of metalloproteinase CD163 ectodomain shedding inhibitors based on azasugar hydroxamic acid scaffold has been synthesized. Among the synthesized compounds, the benzyl derivative 4a and the methyl derivative 4f exhibits 66 and 51 % inhibition, res

Full text of DOI:10.1002/ejoc.200700178

FULL PAPER
DOI: 10.1002/ejoc.200700178
Design, Synthesis and Biological Activity of Azasugar-Based CD163
Ectodomain Shedding Inhibitors
Mohamed I. Attia,[a] Meike Timmermann,[b] Petra Högger,[b] and Claus Herdeis*[a]
Keywords: Hydroxamic acid / Azasugar / Wittig reaction / Metalloproteinase
A series of metalloproteinase CD163 ectodomain shedding
inhibitors based on azasugar hydroxamic acid scaffold has
been synthesized. Among the synthesized compounds, the
benzyl derivative 4a and the methyl derivative 4f exhibits 66
and 51% inhibition, respectively, at 1 µ
CD163 shedding from human monocytes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
M concentration on
Introduction
CD163 is a membrane glycoprotein of the cysteine-rich
scavenger receptor (SRCR) superfamily. It is expressed ex-
clusively on human monocytes and macrophages.[1] CD163
has a function in host defence and homeostasis and serves
as a scavenger receptor for haemoglobin-haptoglobin com-
plexes. CD163 is subjected to proteinase-mediated ectodo-
main shedding upon an inflammatory stimulus in vitro and
it also exists as a soluble protein. Shedding of CD163 is
mediated by a TIMP-3-sensitive metalloproteinase.[2,3] This
shedding-inducing proteinase is attributed to the ADAM
family (a desintegrin and metalloproteinase) with TACE
(TNFα converting enzyme) as prominent member. Thus,
CD163 might serve as a model molecule for a membrane
protein undergoing metalloproteinase-mediated ectodo-
main shedding and it could be an attractive target for me-
dicinal chemists.
Azasugar scaffold containing hydroxamic acid moiety is
a well-known class of compounds possessing metalloprotei-
nase inhibitor activity (1–3, Figure 1).[4] All of them possess
the structural features of pipecolic acid derivatives.
In the present report, we describe the design and synthe-
sis of certain azasugar-containing hydroxamic acid func-
tionalities based on homopipecolic acid derivatives to be
evaluated as CD163-shedding inhibitors. The stereochemis-
try of the azasugar moiety, derived from -ribose in a modi-
fied manner, of the target compounds 4a–g was assigned to
be 3ЈaS,4ЈR,7ЈR,7ЈaR, namely all-cis configuration, which
is in accordance with our previously published results.[5]
Figure 1. Hydroxamic acid derivatives possessing metalloproteinase
inhibitory activities.
Results and Discussion
Chemistry
Synthetic approaches for the preparation of the target
compounds 4a–g and their intermediates are described in
Schemes 1, 2, 3, and 4.
-Ribose contains the required configuration in the 3Јa
and 7Јa positions of the target compounds 4a–g. Thus, -
ribose was transformed to the known isopropylidene deriv-
[a] Pharmazeutische Chemie Division, Würzburg Universität, In-
stitut für Pharmazie und Lebensmittelchemie,
Am Hubland, 97074 Würzburg, Germany
Fax: +49-931-8885494
E-mail: herdeis@pharmazie.uni-wuerzburg.de
[b] Klinische Pharmazie Division, Würzburg Universität,
Am Hubland, 97074 Würzburg, Germany
Eur. J. Org. Chem. 2007, 3669–3675
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M. I. Attia, M. Timmermann, P. Högger, C. Herdeis
FULL PAPER
Scheme 1. (i) TosCl, pyridine; (ii) NaN3, DMSO; (iii) Ph3P=CHCO2CH3, Rh2(OAc)4, Et3N, CH2CL2; (iv) H2, Pd/C, CH3OH.
Scheme 2. (i) NaOH, C2H5OH; (ii) SO2Cl2, DMF.
ative 6 according to the published procedure.[6] Selective to-
sylation of 6 has previously been reported.[7] We employed
the reaction under slightly different conditions obtaining
monotosylate 7 in 75% yield. Subsequently, the tosylate de-
rivative 7 was subjected to nucleophilic substitution using
Scheme 4.
sodium azide in DMSO to furnish azidolactol 8 in 85% line 9a which was not isolated but isomerised to give di-
yield. When 8 was treated with (methoxycarbonylmethyl- azoamine 9b as a single diastereomer. Compound 9b was
ene)triphenylphosphorane at ambient temperature
a
subjected to nitrogen extrusion using rhodium acetate cata-
smooth Wittig reaction took place. This reaction is followed lyst with concomitant 1,2-H shift to provide vinylogous
by an intramolecular [2+3] cycloaddition reaction of the az- urethane 10. This four-step reaction sequence was then
ide functionality to the double bond to produce the triazo- upscaled as a one-pot reaction in 52% yield based on 8.
Scheme 3. (i) K2CO3, CH3CN; (ii) NH2OK, CH3OH.
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Eur. J. Org. Chem. 2007, 3669–3675

Azasugar-Based Ectodomain Shedding Inhibitors
FULL PAPER
Thus, an optimized procedure for the preparation of the compounds 4a and 4f are the most active congeners as com-
vinylogous urethane 10 on a multi-gram scale using cheap pared to the commercially available hydroxamate-based
and commercially available starting material has been suc- metalloproteinase inhibitor TAPI-1.[10]
cessfully achieved. Vinylogous urethane 10 was synthesized
previously[8] by adopting tandem retro-Michael [3+2]-cyclo-
Table 1. CD163 shedding inhibitory activities of 4a–g.
addition on ε-sugar amino acids obtained from -ribose in
four steps. The double bond of 10 was hydrogenated over
10% Pd/C under 55 bar of hydrogen in methanol to afford
the homopipecolic acid derivative 11 (Scheme 1). Com-
pound 11 possesses exclusively R-configuration at C-4 posi-
tion which is a prerequisite for the metalloproteinase inhibi-
tors.[4c]
Gribble et al. reported the synthesis of 4-(benzyloxy)ben-
zenesulfonyl chloride derivatives in a patent literature.[9]
Thus, bis(4-hydroxyphenyl) disulfide was treated with ben-
zyl bromide derivatives in DMF to afford bis[4-(benzyloxy-
phenyl)] disulfide derivatives which were subsequently oxi-
dised to give the corresponding 4-(benzyloxy)benzene-
sulfonyl chloride derivatives using N-chlorosuccinimide in
acetic acid.
We developed a simple alternative route to achieve 4-
(benzyloxy)benzenesulfonyl chloride derivatives 15a–e.
Therefore, disodium salt formation of the commercially
available 4-hydroxyphenylsulfonic acid 12 followed by in-
situ monobenzylation with benzyl bromide derivatives 13a–
e furnished the respective ether derivatives 14a–e in 62–96%
yield. Compounds 14a–e were elaborated to the corre-
sponding sulfonyl chloride derivatives 15a–e through reac-
tion with thionyl chloride in DMF (Scheme 2).
Compound
R
% inhibition
(CD163)ϮSD[a]
4a
benzyl
66Ϯ1.96
40Ϯ8.05
34Ϯ1.61
17Ϯ9.83
35Ϯ2.62
51Ϯ4.84
28Ϯ3.64
95Ϯ0.64
4b
2-methylbenzyl
4-bromobenzyl
4-nitrobenzyl
3-chlorobenzyl
methyl
4c
4d
4e
4f
4g
H
TAPI-1[b]
[a] Standard deviation; the values are the means ϮSD (n = 6). [b]
From Merck Biosciences GmbH, Bad Soden, Germany.
Sulfonylation of the amino ester 11 with 15a–f in acetoni-
trile using K2CO3 afforded sulfonamides 16a–f in 76–90%
yield. Compounds 16a–f were transformed into the corre-
sponding hydroxamic acid derivatives 4a–f (Table 1) in
moderate yields as depicted in Scheme 3.
Furthermore, hydrogenolysis of the benzyl ether of 4d
gave compound 4g in 67% yield (Scheme 4).
Conclusions
A convenient four-step reaction sequence was developed
to achieve vinylogous urethane 10 on multi-gram scale and
as one-pot reaction. Compound 10 was further elaborated
to the novel hydroxamic acid derivatives 4a–g. A straight-
forward route to 4-(benzyloxy)benzenesulfonyl chloride de-
rivatives 15a–e is also reported. The new azasugar-based
hydroxamic acid derivatives 4a–g revealed significant ac-
tivity towards a shedding-inducing metalloproteinase with
4a and 4f being the most potent compounds. Thus, inhibi-
tion of CD163-shedding is a valuable tool for screening and
optimization of new metalloproteinase inhibitors and might
lead to further insights into biological regulation and signi-
ficance of membrane protein-shedding reactions.
Biological Evaluation
Isolation and Culture of Blood Monocytes
Human monocytes were isolated from blood cell suspen-
sions pooled from different donors by Biocoll and subse-
quent Ficoll density gradient centrifugation.[1]
Experimental Section
Shedding Experiments and Flow Cytometric Analysis
(FACS)
General: Melting points were determined on Büchi capillary melt-
ing point apparatus and are uncorrected. IR spectra, recorded as
ATR, were obtained by using a Biorad PharmalyzIR FT-IR spec-
2ϫ106 cells were pre-stimulated for 30 min in the pres-
ence or absence of the inhibitors in a concentration of 1 µ.
1 m H2O2 was added to each well, followed by an incu-
bation period of 30 min. Cells were incubated with the
CD163-specific antibody RM3/1 followed by an incubation
with FITC-labeled secondary antibody goat anti-mouse
IgG1. The fluorescence intensity of 10.000 living cells was
measured by FACS analysis.[3] Table 1 shows the inhibition
1
trometer. 400-MHz H and 100-MHz 13C-NMR spectra were de-
termined on a Bruker AV-400 spectrometer. The chemical shifts are
reported in ppm on δ scales. Mass spectra were acquired in the
positive ion mode under electrospray ionization (ESI) on a LC/
MSD Ion Trap system. Column chromatography was carried out
on silica gel 60 (0.063–0.200 m) obtained from Merck. Combus-
tion analyses were performed by the microanalytical section of the
activity of compounds 4a–g on CD163 shedding where Institute of Inorganic Chemistry, University of Würzburg.
Eur. J. Org. Chem. 2007, 3669–3675
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M. I. Attia, M. Timmermann, P. Högger, C. Herdeis
FULL PAPER
(3aR,4R,6aR)-2,2-Dimethyl-6-(tosyloxymethyl)-tetrahydro-2H-furo-
[3,4-d]-1,3-dioxol-4-ol (7): A solution of TsCl (5.7 g, 30.0 mmol) in
pyridine (10 mL) was added dropwise to a mixture of 6 (5.2 g,
(10.0 mmol) in ethanol (25 mL) was added to a stirred solution
of 65% 4-hydroxybenzenesulfonic acid 12 (2 mL, 10.0 mmol) and
sodium hydroxide (0.8 g, 20.0 mmol) in water (25 mL). The reac-
27.3 mmol) in pyridine (10 mL) at –30 °C. The resulting mixture tion mixture was heated at 100 °C for 18 h, cooled and filtered. The
was stirred at 0 °C for one hour and then at 25 °C for 4 h. Ethyl
acetate (100 mL) was added and the resulting solution was ex-
tracted with 10% H2SO4 (4ϫ20 mL). The organic layer was sepa-
rated, washed with NaHCO3 (3ϫ15 mL), dried (Na2SO4) and the
solvents evaporated under vacuum. The residue was recrystallized
from CH2Cl2/n-pentane to give 7.06 g (75%) of 7 as a white solid
m.p. 95–96 °C. The spectroscopic data of 7 were identical to those
previously reported.[7]
collected solid was washed with cold ethanol (2ϫ10 mL) and dried
to give 14a–e which were pure enough to be used in the next step
without further purification.
Sodium 4-(Benzyloxy)benzenesulfonate (14a):[11] Following the ge-
neral procedure 1.78 g (62%) of 14a was obtained as a white solid
m.p. 296–298 °C. FT-IR (ATR): ν = 3061, 1595, 1497, 1180, 857,
˜
621 cm–1. 1H NMR ([D6]DMSO): δ = 5.12 (s, 2 H, -CH2-C6H5),
6.95 (d, J = 8.8 Hz, 2 H, ArH), 7.31–7.46 (m, 5 H, ArH), 7.55 (d,
(3aR,6R,6aR)-6-(Azidomethyl)-2,2-dimethyl-tetrahydro-2H-furo- J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 69.2
[3,4-d]-1,3-dioxol-4-ol (8): To a stirred solution of 7 (19.0 g,
55.18 mmol) in DMSO (300 mL) was added sodium azide (7.2 g,
110.52 mmol) at room temperature. The reaction mixture was
heated at 75 °C for 18 h. The reaction mixture was cooled, poured
into water (600 mL) and extracted with diethyl ether (3ϫ200 mL).
The organic extracts were combined, dried (Na2SO4) and evapo-
rated under reduced pressure to afford 10.09 g (85%) of 8 as a pale
yellow viscous oil which was pure enough to be used in the next
step without further purification. The spectroscopic data of 8 were
identical to those previously reported.[5]
(-CH2 -C6H5), 113.7, 116.3, 127.1, 127.6, 127.8, 128.4 (ArCH),
136.9, 140.9, 153.3 (ArC) ppm.
Sodium 4-(2-Methylbenzyloxy)benzenesulfonate (14b): Following
the general procedure 1.92 g (64%) of 14b was obtained as a white
solid m.p. 272–273 °C. FT-IR (ATR): ν = 3529, 3474, 1598, 1499,
˜
1176, 833, 698 cm–1. 1H NMR ([D6]DMSO): δ = 2.32 (s, 3 H, CH3),
5.09 (s, 2 H, -CH2-C6H4), 6.98 (d, J = 8.6 Hz, 2 H, ArH), 7.18–
7.25 (m, 3 H, ArH), 7.39–7.41 (m, 1 H, ArH), 7.57 (d, J = 8.6 Hz,
2 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 18.4 (CH3), 67.9
(-CH2-C6H4), 113.6, 114.0, 125.7, 127.1, 128.0, 128.4, 130.1
(ArCH), 134.8, 136.5, 140.9, 157.6, 158.5 (ArC) ppm.
Methyl (3aS,4Z,7R,7aR)-2-[Tetrahydro-7-hydroxy-2,2-dimethyl-1,3-
dioxolo[4,5-c]pyridin-4(5H)-ylidene]acetate (10): To a stirred solu-
tion of 8 (11.19 g, 52.0 mmol) in dry CH2Cl2 (150 mL) was added
Sodium 4-(4-Bromobenzyloxy)benzenesulfonate (14c): Following the
general procedure 2.81 g (77%) of 14c was obtained as a white solid
(methoxycarbonylmethylene)triphenylphosphorane
(17.39 g,
m.p. Ͼ 300 °C. FT-IR (ATR): ν = 3528, 3471, 1593, 1497, 1181,
˜
52.0 mmol). The reaction mixture was stirred at room temperature
for 72 h (TLC-controlled). Triethylamine (14.62 mL, 104.0 mmol)
and rhodium acetate (80 mg) were added and the reaction mixture
was stirred for further 24 h at room temperature. The solvent was
evaporated under vacuum and the residue was recrystallized from
methanol to yield 6.63 g (52%) of 10 as a white solid m.p. 162–
807, 697 cm–1. 1H NMR ([D6]DMSO): δ = 5.11 (s, 2 H, -CH2-
C6H4), 6.94 (d, J = 8.8 Hz, 2 H, ArH), 7.39–7.45 (m, 2 H, ArH),
7.53–7.60 (m, 4 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 68.4
(-CH2-C6H4), 113.7, 113.9, 127.1, 129.7, 131.3 (ArCH), 136.5,
139.1, 141.1, 157.5, 158.1 (ArC) ppm.
163 °C. [α]2D5 = +71.8 (c = 1.0, CHCl ). FT-IR (ATR): ν = 3292,
Sodium 4-(4-Nitrobenzyloxy)benzenesulfonate (14d): Following the
general procedure 2.65 g (80%) of 14d was obtained as a pale yel-
˜
3
2981, 1656, 1607, 1246, 787, 678 cm–1. 1H NMR ([D6]DMSO): δ =
1.32 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 3.09–3.19 (m, 2 H, 6-H),
3.51 (s, 3 H, OCH3), 3.62–3.74 (m, 1 H, 7-H), 4.39 (dd, J = 6.8,
3.0 Hz, 1 H, 7a-H), 4.53 (s, 1 H, 2Ј-H), 4.59 (d, J = 6.8 Hz, 1 H,
3a-H), 5.09 (d, J = 5.6 Hz, 1 H, OH), 8.33 (s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO): δ = 24.5 (CH3), 26.1 (CH3), 40.8 (C-6), 49.6
(OCH3), 65.9 (C-7), 73.9 (C-7a), 74.4 (C-3a), 82.2 (C-2Ј), 108.9 (C-
2), 157.9 (C-4), 169.5 (O=C) ppm.
low solid m.p. 279–280 °C. FT-IR (ATR): ν = 3660, 3457, 1601,
˜
1166, 831, 690 cm–1. 1H NMR ([D6]DMSO): δ = 5.30 (s, 2 H,
-CH2-C6H4), 6.98 (d, J = 8.8 Hz, 2 H, ArH), 7.57 (d, J = 8.8 Hz,
2 H, ArH), 7.72 (d, J = 8.8 Hz, 2 H, ArH), 8.25 (d, J = 8.8 Hz, 2
H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 68.0 (-CH2-C6H4),
113.8, 114.0, 123.6, 127.1, 128.2 (ArCH), 141.1, 144.9, 146.9, 157.7,
157.9 (ArC) ppm.
Sodium 4-(3-Chlorobenzyloxy)benzenesulfonate (14e): Following the
general procedure 3.08 g (96%) of 14e was obtained as a white solid
Methyl (3aS,4R,7R,7aR)-2-[Hexahydro-7-hydroxy-2,2-dimethyl-1,3-
dioxolo[4,5-c]pyridin-4-yl]acetate (11): A solution of 10 (4.5 g,
18.5 mmol) in methanol (160 mL) was hydrogenated over 10% Pd/
C (0.87 g) under 50 bar of H2 for 72 h at 50 °C. The catalyst was
removed by filtration and the solvent was evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (ethyl acetate/methanol, 9:1) to give 4.00 g (88%) of 11 as a
white solid m.p. 56–58 °C. [α]2D5 = –15.6 (c = 1.0, CHCl3). FT-IR
m.p. Ͼ 300 °C. FT-IR (ATR): ν = 3531, 3472, 1597, 1177, 836,
˜
689 cm–1. 1H NMR ([D6]DMSO): δ = 5.14 (s, 2 H, -CH2-C6H4),
6.96 (d, J = 8.8 Hz, 2 H, ArH), 7.43–7.45 (m, 3 H, ArH), 7.51–
7.52 (m, 1 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR
([D6]DMSO): δ = 68.3 (-CH2-C6H4), 113.7, 114.0, 126.1, 127.1,
127.2, 127.7, 130.4 (ArCH), 133.1, 139.6, 140.9, 157.6, 158.1 (ArC)
ppm.
(ATR): ν = 3482, 3303, 2986, 1726, 1213, 793, 635 cm–1. 1H NMR
˜
(CDCl3): δ = 1.29 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 2.23 (d, J =
2.8 Hz, 1 H, OH), 2.55 (d, J = 7.1 Hz, 2 H, 2Ј-H), 2.59 (dd, J =
13.6, 2.0 Hz, 1 H, Ha-6), 3.07 (dd, J = 13.6, 4.0 Hz, 1 H, Hb-6),
3.23 (ddd, J = 7.1, 6.8, 2.8 Hz, 1 H, 7-H), 3.62–3.63 (m, 1 H, 4-
General Procedure for the Synthesis of Arylsulfonyl Chloride Deriva-
tives (15a–e): Thionyl chloride (0.67 mL, 9.16 mmol) was added
dropwise to a stirred suspension of the appropriate sodium arylsul-
fonate derivative 14a–e (7.0 mmol) in dry DMF (20 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 5 min, poured onto ice, stirred further for 5 min and the precipi-
tated solid was filtered. The collected solid was dissolved in CH2Cl2
(20 mL) and washed with water (2ϫ10 mL). The organic layer was
separated, dried (Na2SO4) and the solvents evaporated under vac-
uum to afford 15a–e which were used directly without further puri-
fication.
H), 3.64 (s, 3 H, OCH3), 4.05–4.09 (m, 2 H, 3a-H, 7a-H) ppm. 13
C
NMR (CDCl3): δ = 25.2 (CH3), 25.9 (CH3), 36.8 (C-2Ј), 48.0 (C-
6), 51.7 (C-7), 52.5 (OCH3), 63.4 (C-4), 72.9, 74.1 (C-3a, C-7a),
108.9 (C-2), 172.4 (O=C) ppm. C11H19NO5 (245.27): calcd. C
53.87, H 7.81, N 5.71; found C 53.63, H 7.52, N 5.54.
General Procedure for the Synthesis of Arylsulfonic Acid Derivatives
14a–e: The appropriate benzyl bromide derivative 13a–e
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Eur. J. Org. Chem. 2007, 3669–3675

Azasugar-Based Ectodomain Shedding Inhibitors
FULL PAPER
4-Benzyloxybenzenesulfonyl chloride (15a):[11] Following the general
procedure 1.25 g (63%) of 15a was obtained as a white solid m.p.
(16a): Following the general procedure 0.38 g (78%) of 16a was
obtained as a white solid m.p. 94–96 °C. [α]2D5 = –19.2 (c = 0.5,
103–105 °C. FT-IR (ATR): ν = 3534, 1572, 1491, 1159, 698 cm–1.
MeOH). FT-IR (ATR): ν = 3487, 1726, 1591, 1146, 706, 610 cm–1.
˜
˜
1H NMR ([D6]DMSO): δ = 5.10 (s, 2 H, -CH2-C6H5), 6.96 (d, J =
8.8 Hz, 2 H, ArH), 7.28–7.45 (m, 5 H, ArH), 7.55 (d, J = 8.8 Hz,
1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.39 (s, 3 H, CH3),
2.50–2.53 (m, 1 H, Ha-2Ј), 2.83 (dd, J = 16.0, 7.9 Hz, 1 H, Hb-2Ј),
2 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 69.2 (-CH2-C6H5), 2.99 (dd, J = 13.2, 10.6 Hz, 1 H, Ha-6), 3.32–3.38 (m, 7-H, 2 H,
113.8, 127.1, 127.6, 127.8, 128.4 (ArCH), 136.9, 140.1, 153.6 (ArC)
ppm.
4-(2-Methylbenzyloxy)benzenesulfonyl Chloride (15b):[9] Following
the general procedure 1.39 g (67%) of 15b was obtained as a white
Hb-6), 3.53 (s, 3 H, OCH3), 4.24–4.27 (m, 1 H, 4-H), 4.29–4.33 (m,
2 H, 3a-H, 7a-H), 5.18 (d, J = 5.0 Hz, 1 H, OH), 5.21 (s, 2 H,
-CH2-C6H5), 7.23 (d, J = 8.8 Hz, 2 H, ArH), 7.34 (m, 5 H, ArH),
7.75 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR ([D6]DMSO): δ =
24.6 (CH3), 25.4 (CH3), 36.1 (C-2Ј), 42.3 (C-6), 50.1 (C-4), 51.3
(OCH3), 63.8 (C-7), 69.7 (-CH2-C6H5), 72.6, 73.2 (C-3a, C-7a),
108.4 (C-2) 115.5, 127.9, 128.1, 128.5, 129.1 (ArCH), 130.9, 136.2,
161.8 (ArC), 170.9 (O=C) ppm. C24H29NO8S (491.55): calcd. C
58.64, H 5.95, N 2.85; found C 58.34, H 5.66, N 2.76.
solid m.p. 114–115 °C. FT-IR (ATR): ν = 3655, 1583, 1491, 1161,
˜
1
683 cm–1. H NMR ([D6]DMSO): δ = 2.31 (s, 3 H, CH3), 5.09 (s,
2 H, -CH2-C6H4), 6.99 (d, J = 8.8 Hz, 2 H, ArH), 7.16–7.26 (m, 3
H, ArH), 7.38–7.39 (m, 1 H, ArH), 7.57 (d, J = 8.8 Hz, 2 H, ArH)
ppm. 13C NMR ([D6]DMSO): δ = 18.4 (CH3), 67.9 (-CH2-C6H4),
113.8, 125.7, 127.1, 128.0, 128.4, 130.1 (ArCH), 134.7, 136.5, 139.9,
158.8 (ArC) ppm.
4-(4-Bromobenzyloxy)benzenesulfonyl Chloride (15c):[9] Following
the general procedure 1.92 g (76%) of 15c was obtained as a white
Methyl (3aS,4R,7R,7aR)-2-[Hexahydro-7-hydroxy-2,2-dimethyl-5-
[4-(2-methylbenzyloxy)phenylsulfonyl]-1,3-dioxolo[4,5-c]pyridin-4-yl-
]acetate (16b): Following the general procedure 0.46 g (90%) of 16b
was obtained as a white solid m.p. 156–158 °C. [α]2D5 = +9.5 (c =
solid m.p. 100–102 °C. FT-IR (ATR): ν = 3578, 1657, 1588, 1493,
˜
0.2, MeOH). FT-IR (ATR): ν = 3433, 1713, 1589, 1148, 756,
˜
1155, 623 cm–1. 1H NMR ([D6]DMSO): δ = 5.10 (s, 2 H, -CH2-
C6H4), 6.95 (d, J = 8.8 Hz, 2 H, ArH), 7.39–7.41 (m, 2 H, ArH),
7.53–7.59 (m, 4 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 68.4
(-CH2-C6H4), 113.9, 127.1, 129.7, 131.3 (ArCH), 120.9, 136.4,
140.2, 158.4 (ArC) ppm.
1
678 cm–1. H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.39 (s,
3 H, CH3), 2.33 (s, 3 H, H3C-C6H4), 2.53–2.55 (m, 1 H, Ha-2Ј),
2.85–2.89 (m, 1 H, Hb-2Ј), 2.90–2.94 (m, 1 H, Ha-6), 3.37–3.42 (m,
2 H, Hb-6, 7-H), 3.45 (s, 3 H, OCH3), 4.09–4.10 (m, 1 H, 4-H),
4.29–4.33 (m, 2 H, 3a-H, 7a-H), 5.19 (s, 2 H, -CH2-C6H4), 7.22 (d,
J = 8.8 Hz, 2 H, ArH), 7.23–7.26 (m, 3 H, ArH), 7.24–7.43 (m, 1
H, ArH), 7.69 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR ([D6]-
DMSO): δ = 18.4 (H3C-C6H4), 24.6 (CH3), 25.4 (CH3), 36.1 (C-
2Ј), 42.2 (C-6), 50.1 (C-4), 51.3 (OCH3), 63.9 (C-7), 68.7 (-CH2-
C6H4), 72.7, 73.2 (C-3a, C-7a), 108.4 (C-2) 115.2, 125.8, 128.3,
128.7, 129.2, 130.1 (ArCH), 132.5, 134.2, 136.7, 161.6 (ArC), 172.2
(O=C) ppm. C25H31NO8S (505.58): calcd. C 59.39, H 6.18, N 2.77;
found C 59.14, H 6.09, N 2.63.
4-(4-Nitrobenzyloxy)benzenesulfonyl Chloride (15d): Following the
general procedure 1.26 g (55%) of 15d was obtained as a pale yel-
low solid m.p. 152–153 °C. FT-IR (ATR): ν = 3444, 1578, 1516,
˜
1340, 1157, 698 cm–1. 1H NMR ([D6]DMSO): δ = 5.29 (s, 2 H,
-CH2-C6H4), 6.98 (d, J = 8.8 Hz, 2 H, ArH), 7.56 (d, J = 8.8 Hz,
2 H, ArH), 7.70 (d, J = 8.8 Hz, 2 H, ArH), 8.23 (d, J = 8.8 Hz, 2
H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 68.0 (-CH2-C6H4),
113.9, 123.6, 127.2, 128.2 (ArCH), 140.4, 144.9, 146.9, 158.1 (ArC)
ppm.
Methyl (3aS,4R,7R,7aR)-2-[5-[4-(4-Bromobenzyloxy)phenyl-
sulfonyl]-hexahydro-7-hydroxy-2,2-dimethyl-1,3-dioxolo[4,5-c]-
pyridin-4-yl]acetate (16c): Following the general procedure 0.47 g
(82%) of 16c was obtained as a white solid m.p. 144–146 °C. [α]2D5
4-(3-Chlorobenzyloxy)benzenesulfonyl Chloride (15e):[9] Following
the general procedure 1.62 g (73%) of 15e was obtained as a white
solid m.p. 62–63 °C. FT-IR (ATR): ν = 3659, 1659, 1584, 1494,
˜
1157, 679 cm–1. 1H NMR ([D6]DMSO): δ = 5.14 (s, 2 H, -CH2-
C6H4), 6.96 (d, J = 8.8 Hz, 2 H, ArH), 7.36–7.41 (m, 3 H, ArH),
7.50–7.51 (m, 1 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH) ppm.
13C NMR ([D6]DMSO): δ = 68.3 (-CH2-C6H4), 113.9, 126.1, 127.1,
127.2, 127.7, 130.3 (ArCH), 133.1, 139.5, 140.4, 158.3 (ArC) ppm.
= –1.7 (c = 0.12, MeOH). FT-IR (ATR): ν = 3437, 1716, 1591,
˜
1148, 758, 685 cm–1. 1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3),
1.39 (s, 3 H, CH3), 2.52–2.55 (m, 1 H, Ha-2Ј), 2.85–2.88 (m, 1 H,
Hb-2Ј), 2.89–2.91 (m, 1 H, Ha-6), 3.32–3.44 (m, 2 H, Hb-6, 7-H),
3.52 (s, 3 H, OCH3), 4.25–4.26 (m, 1 H, 4-H), 4.28–4.33 (m, 2 H,
3a-H, 7a-H), 5.19 (s, 2 H, -CH2-C6H4), 7.18 (d, J = 8.8 Hz, 2 H,
ArH), 7.44 (d, J = 8.3 Hz, 2 H, ArH), 7.61 (d, J = 8.3 Hz, 2 H,
ArH), 7.68 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR ([D6]-
DMSO): δ = 24.6 (CH3), 25.8 (CH3), 36.1 (C-2Ј), 42.4 (C-6), 50.1
(C-4), 51.3 (OCH3), 63.8 (C-7), 68.7 (-CH2-C6H4), 72.6, 73.3 (C-
3a, C-7a), 108.4 (C-2) 115.5, 128.7, 129.9, 131.4 (ArCH), 121.3,
130.0, 135.7, 161.7 (ArC), 174.4 (O=C) ppm. C24H28BrNO8S
(570.45): calcd. C 50.53, H 4.95, N 2.46; found C 50.29, H 4.83, N
2.08.
4-Methoxybenzenesulfonyl Chloride (15f):[12] Following the litera-
ture procedure[12] 0.72 g (50%) of 15f was obtained as a white solid
m.p. 39–40 °C. FT-IR (ATR): ν = 3451, 1584, 1491, 1152, 626 cm–1.
˜
1H NMR ([D6]DMSO): δ = 3.74 (s, 3 H, OCH3), 6.88 (d, J =
8.8 Hz, 2 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR
([D6]DMSO): δ = 55.2 (OCH3), 113.0, 127.1 (ArCH), 139.3, 159.7
(ArC) ppm.
General Procedure for the Synthesis of Methyl (3aS,4R,7R,7aR)-2-
[5-(4-Arylsulfonyl)-hexahydro-7-hydroxy-2,2-dimethyl-1,3-dioxolo-
[4,5-c]pyridin-4-yl]acetate Derivatives 16a–f: A solution of the ap-
propriate arylsulfonyl chloride derivative 15a–f (1.1 mmol) in dry
acetonitrile (5 mL) was added at room temperature to a stirred sus-
pension of 11 (0.25 g, 1 mmol) and anhydrous K2CO3 (0.22 g,
1.6 mmol) in dry acetonitrile (5 mL). The reaction mixture was vig-
orously stirred at room temperature for 18 h. The reaction mixture
was filtered and the filtrate was evaporated under reduced pressure.
The residue was purified by column chromatography (diethyl ether/
n-pentane, 8:2) to afford 16a–f.
Methyl (3aS,4R,7R,7aR)-2-[Hexahydro-7-hydroxy-2,2-dimethyl-5-
[4-(4-nitrobenzyloxy)phenylsulfonyl]-1,3-dioxolo[4,5-c]pyridin-4-yl]-
acetate (16d): Following the general procedure 0.44 g (82%) of 16d
was obtained as a pale yellow solid m.p. 62–64 °C. [α]2D5 = –13.5 (c
= 0.4, MeOH). FT-IR (ATR): ν = 3600–3400, 1732, 1591, 1151,
˜
837, 648 cm–1. 1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.39
(s, 3 H, CH3), 2.46–2.50 (m, 1 H, Ha-2Ј), 2.83 (dd, J = 16.0, 7.9 Hz,
1 H, Hb-2Ј), 2.99 (dd, J = 13.2, 10.6 Hz, 1 H, Ha-6), 3.34–3.36 (m,
1 H, Hb-6), 3.39–3.43 (m, 1 H, 7-H), 3.53 (s, 3 H, OCH3), 4.24–
4.27 (m, 1 H, 4-H), 4.28–4.33 (m, 2 H, 3a-H, 7a-H), 5.39 (s, 2 H,
Methyl (3aS,4R,7R,7aR)-2-[5-(4-Benzyloxyphenylsulfonyl)-hexahy-
dro-7-hydroxy-2,2-dimethyl-1,3-dioxolo[4,5-c]pyridin-4-yl]acetate -CH2 -C6H4), 7.25 (d, J = 8.8 Hz, 2 H, ArH), 7.74–7.78 (m, 4 H,
Eur. J. Org. Chem. 2007, 3669–3675
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3673

M. I. Attia, M. Timmermann, P. Högger, C. Herdeis
FULL PAPER
ArH), 8.27 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR ([D6]-
10.38 (2 s, 2 H, NH and OH) ppm. 13C NMR ([D6]DMSO): δ =
DMSO): δ = 24.6 (CH3), 25.8 (CH3), 36.1 (C-2Ј), 42.4 (C-6), 50.1 24.6 (CH3), 25.8 (CH3), 34.2 (C-2), 42.6 (C-6Ј), 49.9 (C-4Ј), 63.9
(C-4), 51.3 (OCH3), 63.8 (C-7), 68.7 (-CH2-C6H4), 72.6, 73.3 (C- (C-7Ј), 69.8 (-CH2-C6H5), 72.9, 73.3 (C-3Јa, C-7Јa), 108.0 (C-2Ј)
3a, C-7a), 108.4 (C-2) 115.5, 128.7, 129.9, 131.4 (ArCH), 121.3, 115.3, 127.9, 128.1, 128.5, 129.3 (ArCH), 130.7, 136.2, 161.7 (ArC),
130.0, 135.7, 161.7 (ArC), 174.4 (O=C) ppm. C24H28N2O10
(536.55): calcd. C 53.72, H 5.26, N 5.22; found C 53.38, H 4.89, N
5.12.
S
166.5 (O=C) ppm. ESI MS: m/z = 493.4 [M + 1]+. C23H28N2O8S
(492.54): calcd. C 56.09, H 5.73, N 5.69; found C 55.84, H 5.33, N
5.36.
Methyl (3aS,4R,7R,7aR)-5-[4-(3-Chlorobenzyloxy)phenylsulfonyl]-
hexahydro-7-hydroxy-2,2-dimethyl-1,3-dioxolo[4,5-c]piperid-4-yl]-
acetate (16e): Following the general procedure 0.39 g (76%) of 16e
was obtained as white solid m.p. 65–67 °C. [α]2D5 = –16.0 (c = 0.5,
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-Hexahydro-7Ј-hydroxy-2Ј,2Ј-dimethyl-5Ј-[4-
(2-methylbenzyloxy)phenylsulfonyl]-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl-
]acetohydroxamic Acid (4b): Following the general procedure 0.38 g
(86%) of 4b was obtained as a pale yellow solid m.p. 172–173 °C.
[α]2D5 = –19.25 (c = 0.4, MeOH). FT-IR (ATR): ν = 3418, 3258,
MeOH). FT-IR (ATR): ν = 3400–3200, 1732, 1591, 1151, 682,
˜
˜
1
609 cm–1. H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.39 (s,
1
1665, 1591, 1150, 745, 617 cm–1. H NMR ([D6]DMSO): δ = 1.25
3 H, CH3), 2.50–2.52 (m, 1 H, Ha-2Ј), 2.84 (dd, J = 16.2, 7.8 Hz,
1 H, Hb-2Ј), 2.99 (dd, J = 13.2, 10.5 Hz, 1 H, Ha-6), 3.37–3.39 (m,
1 H, Hb-6), 3.43–3.48 (m, 1 H, 7-H), 3.53 (s, 3 H, OCH3), 4.25–
4.27 (m, 1 H, 4-H), 4.28–4.33 (m, 2 H, 3a-H, 7a-H), 5.23 (s, 2 H,
-CH2-C6H4), 7.23 (d, J = 8.8 Hz, 2 H, ArH), 7.41–7.47 (m, 3 H,
ArH), 7.45–7.56 (m, 1 H, ArH), 7.76 (d, J = 8.8 Hz, 2 H, ArH)
ppm. 13C NMR ([D6]DMSO): δ = 24.6 (CH3), 25.4 (CH3), 36.0 (C-
2Ј), 42.3 (C-6), 50.1 (C-4), 51.3 (OCH3), 63.9 (C-7), 68.8 (-CH2-
C6H4), 72.7, 73.3 (C-3a, C-7a), 108.4 (C-2), 115.5, 126.4, 127.5,
128.0, 129.1, 130.4 (ArCH), 131.1, 133.2, 138.8, 161.5 (ArC), 170.9
(O=C) ppm. C24H28ClNO8S (525.99): calcd. C 54.80, H 5.37, N
2.66; found C 54.73, H 5.26, N 2.54.
(s, 3 H, CH3), 1.42 (s, 3 H, CH3), 2.34 (s, 3 H, H3C-C6H4), 2.51–
2.53 (m, 2 H, 2-H), 3.01 (dd, J = 14.3, 12.3 Hz, 1 H, Ha-6Ј), 3.29–
3.35 (m, 2 H, Hb-6Ј, 7Ј-H), 4.17–4.22 (m, 1 H, 4Ј-H), 4.23–4.33 (m,
2 H, 3Јa-H, 7Јa-H), 5.03 (d, J = 5.6 Hz, 1 H, OH), 5.19 (s, 2 H,
-CH2-C6H5), 7.23 (d, J = 8.8 Hz, 2 H, ArH), 7.26–7.27 (m, 3 H,
ArH), 7.43–7.44 (m, 1 H, ArH), 7.77 (d, J = 8.8 Hz, 2 H, ArH),
8.72, 10.37 (2 s, 2 H, NH and OH) ppm. 13C NMR ([D6]DMSO):
δ = 18.4 (H3C-C6H4), 24.6 (CH3), 25.8 (CH3), 34.2 (C-2), 42.6 (C-
6Ј), 49.9 (C-4Ј), 63.9 (C-7Ј), 68.4 (-CH2-C6H5), 72.9, 73.3 (C-3Јa,
C-7Јa), 108.0 (C-2Ј), 115.3, 128.7, 129.3, 130.2 (ArCH), 130.7,
134.1, 136.7, 161.8 (ArC), 166.5 (O=C) ppm. ESI MS: m/z = 507.4
[M + 1]+. C24H30N2O8S (506.57): calcd. C 56.90, H 5.97, N 5.53;
found C 56.83, H 5.76, N 5.28.
Methyl (3aS,4R,7R,7aR)-2-[Hexahydro-7-hydroxy-5-(4-methoxy-
phenylsulfonyl)-2,2-dimethyl-1,3-dioxolo[4,5-c]pyridin-4-yl]acetate
(16f): Following the general procedure 0.33 g (80%) of 16f was ob-
tained as colorless viscous oil. [α]2D5 = –20.6 (c = 0.5, MeOH). FT-
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-5Ј-[4-(4-Bromobenzyloxy)phenylsulfonyl]-
hexahydro-7Ј-hydroxy-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-
yl]acetohydroxamic Acid (4c): Following the general procedure
0.35 g (71%) of 4c was obtained as a white solid m.p. 193–194 °C.
IR (ATR): ν = 3499, 1733, 1596, 1150, 805, 672 cm–1. 1H NMR
˜
([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 2.51–2.53
(m, 1 H, Ha-2Ј), 2.83 (dd, J = 16.3, 8.2 Hz, 1 H, Hb-2Ј), 2.99 (dd,
J = 13.1, 10.4 Hz, 1 H, Ha-6), 3.33–3.45 (m, 2 H, Hb-6, 7-H), 3.55
(s, 3 H, CO2CH3), 3.86 (s, 3 H, OCH3), 4.24–4.26 (m, 1 H, 4-H),
4.28–4.32 (m, 2 H, 3a-H, 7a-H), 5.14 (d, J = 5.3 Hz, 1 H, OH),
7.14 (d, J = 8.8 Hz, 2 H, ArH), 7.75 (d, J = 8.8 Hz, 2 H, ArH)
ppm. 13C NMR ([D6]DMSO): δ = 24.5 (CH3), 25.4 (CH3), 36.1 (C-
2Ј), 42.4 (C-6), 50.1 (C-4), 51.3 (CO2CH3), 55.7 (OCH3), 63.8 (C-
7), 72.7, 73.2 (C-3a, C-7a), 108.4 (C-2), 114.7, 129.1, (ArCH),
130.6, 162.7 (ArC), 170.9 (O=C) ppm. C18H25NO8S (415.46):
calcd. C 52.04, H 6.07, N 3.37; found C 51.75, H 5.99, N 3.18.
[α]2D5 = –20.75 (c = 0.4, MeOH). FT-IR (ATR): ν = 3509, 3247,
˜
1
1645, 1589, 1153, 723, 634 cm–1. H NMR ([D6]DMSO): δ = 1.25
(s, 3 H, CH3), 1.42 (s, 3 H, CH3), 2.50–2.53 (m, 2 H, 2-H), 3.01
(dd, J = 14.4, 12.38 Hz, 1 H, Ha-6Ј), 3.28–3.39 (m, 2 H, Hb-6Ј, 7Ј-
H), 4.16–4.21 (m, 1 H, 4Ј-H), 4.22–4.36 (m, 2 H, 3Јa-H, 7Јa-H),
5.02 (d, J = 5.3 Hz, 1 H, OH), 5.19 (s, 2 H, -CH2-C6H5), 7.20 (d,
J = 8.8 Hz, 2 H, ArH), 7.45 (d, J = 8.5 Hz, 2 H, ArH), 7.62 (d, J
= 8.5 Hz, 2 H, ArH), 7.76 (d, J = 8.8 Hz, 2 H, ArH), 8.71, 10.36
(2 s, 2 H, NH and OH) ppm. 13C NMR ([D6]DMSO): δ = 24.6
(CH3), 25.8 (CH3), 34.2 (C-2), 42.6 (C-6Ј), 49.9 (C-4Ј), 63.9 (C-7Ј),
69.9 (-CH2-C6H5), 72.9, 73.3 (C-3Јa, C-7Јa), 108.0 (C-2Ј), 115.3,
129.3, 130.0, 131.4 (ArCH), 121.3, 130.1, 135.7, 161.5 (ArC), 166.5
(O=C) ppm. ESI MS: m/z = 572.2 [M + 1]+. C23H27BrN2O8S
(571.44): calcd. C 48.34, H 4.76, N 4.90; found C 47.98, H 4.69, N
4.76.
General Procedure for the Synthesis of [(3ЈaS,4ЈR,7ЈR,7ЈaR)-5Ј-(4-
Arylsulfonyl)-7Ј-hydroxy-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridine-
4Ј-yl]acetohydroxamic Acid Derivatives 4a–f: A solution of 1.25 
NH2OK (2 mL; prepared from NH2OH·HCl and KOH as de-
scribed in the literature[13]) was added dropwise to a stirred solution
of the appropriate methyl ester 16a–f (0.86 mmol) in methanol
(4 mL). The resulting reaction mixture was stirred at room tem-
perature for 18 h. The solvent was evaporated under reduced pres-
sure and the residue was recrystallized from chloroform to give 4a–
f.
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-Hexahydro-7Ј-hydroxy-2Ј,2Ј-dimethyl-5Ј-[4-
(4-nitrobenzyloxy)phenylsulfonyl]-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl]-
acetohydroxamic Acid (4d): Following the general procedure 0.36 g
(77%) of 4d was obtained as a yellow solid m.p. 138–140 °C. [α]2D5
= –23.75 (c = 0.4, MeOH). FT-IR (ATR): ν = 3442, 1663, 1594,
˜
1153, 702, 647 cm–1. 1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3),
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-5Ј-(4-Benzyloxyphenylsulfonyl)-hexahydro- 1.42 (s, 3 H, CH3), 2.50–2.54 (m, 2 H, 2-H), 2.97–3.03 (m, 1 H,
7Ј-hydroxy-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl]acetohy-
droxamic Acid (4a): Following the general procedure 0.3 g (71%)
of 4a was obtained as a white solid m.p. 173–175 °C. [α]2D5 = –20.25
Ha-6Ј), 3.27–3.33 (m, 2 H, Hb-6Ј, 7Ј-H), 4.17–4.20 (m, 1 H, 4Ј-H),
4.22–4.32 (m, 2 H, 3Јa-H, 7Јa-H), 5.03 (d, J = 5.3 Hz, 1 H, OH),
5.39 (s, 2 H, -CH2-C6H5), 7.23 (d, J = 8.8 Hz, 2 H, ArH), 7.75–
7.79 (m, 4 H, ArH), 8.28 (d, J = 8.8 Hz, 2 H, ArH), 8.71, 10.36 (2
(c = 0.4, MeOH). FT-IR (ATR): ν = 3515, 3443, 1667, 1589, 1152,
˜
704, 611 cm–1. 1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.42 s, 2 H, NH and OH) ppm. 13C NMR ([D6]DMSO): δ = 24.6 (CH3),
(s, 3 H, CH3), 2.51–2.53 (m, 2 H, 2-H), 3.01 (dd, J = 14.3, 12.2 Hz, 25.8 (CH3), 34.1 (C-2), 42.5 (C-6Ј), 49.9 (C-4Ј), 63.9 (C-7Ј), 68.5
1 H, Ha-6Ј), 3.28–3.35 (m, 2 H, Hb-6Ј, 7Ј-H), 4.17–4.19 (m, 1 H, (-CH2-C6H5), 73.0, 73.3 (C-3Јa, C-7Јa), 108.1 (C-2Ј) 115.4, 123.7,
4Ј-H), 4.22–4.32 (m, 2 H, 3Јa-H, 7Јa-H), 5.02 (d, J = 5.6 Hz, 1 H,
OH), 5.20 (s, 2 H, -CH2-C6H5), 7.21 (d, J = 8.8 Hz, 2 H, ArH),
7.35–7.49 (m, 5 H, ArH), 7.76 (d, J = 8.8 Hz, 2 H, ArH), 8.72,
128.4, 129.4 (ArCH), 131.1, 144.1, 147.2, 161.3 (ArC), 166.4 (O=C)
ppm. ESI MS: m/z = 538.3 [M + 1]+. C23H27N3O10S (537.54):
calcd. C 51.39, H 5.06, N 7.82; found C 51.01, H 4.87, N 7.56.
3674
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3669–3675

Azasugar-Based Ectodomain Shedding Inhibitors
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-5Ј-[4-(3-Chlorobenzyloxy)phenylsulfonyl]-7Ј- H, ArH), 8.23, 9.85 (2 s, 2 H, NH and OH) ppm. 13C NMR ([D6]-
FULL PAPER
hydroxy-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl]aceto-
hydroxamic Acid (4e): Following the general procedure 0.39 g
DMSO): δ = 24.5 (CH3), 25.8 (CH3), 34.3 (C-2), 42.7 (C-6Ј), 49.6
(C-4Ј), 63.8 (C-7Ј), 72.9, 73.4 (C-3Јa, C-7Јa), 107.8 (C-2Ј), 116.3,
129.4, (ArCH), 125.7, 164.5 (ArC), 166.6 (O=C) ppm. ESI MS:
m/z = 403.3 [M + 1]+. C16H22N2O8S (402.42): calcd. C 47.75, H
(85%) of 4e was obtained as a white solid m.p. 174–175 °C. [α]2D5
=
–23.25 (c = 0.4, MeOH). FT-IR (ATR): ν = 3445, 3280, 1661, 1593,
˜
1151, 681, 614 cm–1. 1H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 5.51, N 6.96; found C 47.46, H 5.37, N 6.60.
1.42 (s, 3 H, CH3), 2.50–2.52 (m, 2 H, 2-H), 3.01 (dd, J = 14.3,
12.3 Hz, 1 H, Ha-6Ј), 3.28–3.32 (m, 2 H, Hb-6Ј, 7Ј-H), 4.17–4.19
Acknowledgments
(m, 1 H, 4Ј-H), 4.21–4.32 (m, 2 H, 3Јa-H, 7Јa-H), 5.02 (d, J =
5.0 Hz, 1 H, OH), 5.22 (s, 2 H, -CH2-C6H5), 7.22 (d, J = 8.8 Hz, 2
We thank Dipl.-Chem. S. Ries for help in the preparation of start-
H, ArH), 7.41–7.46 (m, 3 H, ArH), 7.55–7.59 (m, 1 H, ArH), 7.77
(d, J = 8.8 Hz, 2 H, ArH), 8.71, 10.36 (2 s, 2 H, NH and OH)
ppm. 13C NMR ([D6]DMSO): δ = 24.6 (CH3), 25.8 (CH3), 34.2 (C-
2), 42.6 (C-6Ј), 49.9 (C-4Ј), 63.9 (C-7Ј), 68.8 (-CH2-C6H5), 72.9,
73.3 (C-3Јa, C-7Јa), 108.0 (C-2Ј), 115.3, 126.4, 127.6, 128.0, 129.4,
130.4 (ArCH), 130.9, 133.1, 138.8, 161.5 (ArC), 166.5 (O=C) ppm.
ESI MS: m/z = 527.3 [M + 1]+. C23H27ClN2O8S (526.99): calcd. C
52.42, H 5.16, N 5.32; found C 52.08, H 5.09, N 5.29.
ing materials. We also thank Dr. M. Unger and A. Frank for MS
(ESI) analyses and TauroPharm GmbH for financial support. We
express our gratitude to Mrs. A. Betz for technical assistance.
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2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-Hexahydro-7Ј-hydroxy-5Ј-(4-methoxyphen-
ylsulfonyl)-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl]aceto-
hydroxamic Acid (4f): Following the general procedure 0.22 g (61%)
of 4f was obtained as colorless solid m.p. 149–151 °C. [α]2D5 = –27.0
(c = 0.4, MeOH). FT-IR (ATR): ν = 3441, 3240, 1672, 1596, 1153,
˜
1
673 cm–1. H NMR ([D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.42 (s,
3 H, CH3), 2.50–2.52 (m, 2 H, 2-H), 2.99 (dd, J = 14.2, 12.1 Hz, 1
H, Ha-6Ј), 3.27–3.31 (m, 2 H, Hb-6Ј, 7Ј-H), 3.86 (s, 3 H, OCH3),
4.15–4.21 (m, 1 H, 4Ј-H), 4.22–4.32 (m, 2 H, 3Јa-H, 7Јa-H), 5.02
(br. s, 1 H, OH), 7.13 (d, J = 8.8 Hz, 2 H, ArH), 7.75 (d, J =
8.8 Hz, 2 H, ArH), 8.73, 10.35 (2 s, 2 H, NH and OH) ppm. 13C
NMR ([D6]DMSO): δ = 24.6 (CH3), 25.8 (CH3), 34.2 (C-2), 42.6
(C-6Ј), 49.9 (C-4Ј), 55.7 (OCH3), 63.9 (C-7Ј), 72.9, 73.3 (C-3Јa, C-
7Јa), 108.0 (C-2Ј), 114.6, 129.3, (ArCH), 130.5, 162.6 (ArC), 166.5
(O=C) ppm. ESI MS: m/z = 417.4 [M + 1]+. C17H24N2O8S
(416.45): calcd. C 49.03, H 5.81, N 6.73; found C 48.78, H 5.54, N
6.54.
2-[(3ЈaS,4ЈR,7ЈR,7ЈaR)-Hexahydro-7Ј-hydroxy-5Ј-(4-hydroxyphen-
ylsulfonyl)-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolo[4,5-c]pyridin-4Ј-yl]aceto-
hydroxamic Acid (4g): To a stirred solution of 4d (0.22 g,
0.41 mmol) in methanol (10 mL) was added 10% Pd/C (0.13 g).
The reaction mixture was hydrogenated under normal pressure of
H2 at room temperature for 2 h. The catalyst was removed by fil-
tration and the solvent was evaporated under vacuum. The residue
was recrystallized from chloroform to afford 0.11 g (67%) of 4g as
a white solid m.p. 131–132 °C. [α]2D5 = –20.0 (c = 0.4, MeOH). FT-
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IR(ATR):ν=3400–3350,1652,1584,1151,679 cm–1.1HNMR([D ]-
˜
6
375–378.
DMSO): δ = 1.16 (s, 3 H, CH3), 1.33 (s, 3 H, CH3), 2.51–2.54 (m,
2 H, 2-H), 2.88 (dd, J = 11.5, 9.7 Hz, 1 H, Ha-6Ј), 3.14–3.21 (m, 2
H, Hb-6Ј, 7Ј-H), 4.01–4.05 (m, 1 H, 4Ј-H), 4.13–4.23 (m, 2 H, 3Јa-
H, 7Јa-H), 6.74 (d, J = 8.8 Hz, 2 H, ArH), 7.47 (d, J = 8.8 Hz, 2
[13] C. R. Hauser, W. B. Renfrow, Jr., Org. Synth., Coll. Vol. 1943,
2, 67–68.
Received: February 27, 2007
Published Online: June 8, 2007
Eur. J. Org. Chem. 2007, 3669–3675
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3675