Syntheses of tetrahydroxyazepanes from chiro-inositols and their evaluation as glycosidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2003.10.003

Two pairs of C₂-symmetric tetrahydroxyazepanes [(-), (+)-1 and (-), (+)-2] have been synthesized from the enantiomeric chiro-inositols and evaluated as glycosidase inhibitors. Alternative syntheses of ido-tetrahydroxyazepanes (-)- and (+)-2 fro

Full text of DOI:10.1016/j.bmc.2003.10.003

Bioorganic & Medicinal Chemistry 12 (2004) 225–232
Syntheses of tetrahydroxyazepanes from chiro-inositols
and their evaluation as glycosidase inhibitors
Gavin F. Painter,* Paul J. Eldridge and Andrew Falshaw
Carbohydrate Chemistry, Industrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand
Received 4 September 2003; accepted 5 October 2003
Abstract—Two pairs of C2-symmetric tetrahydroxyazepanes [(ꢀ), (+)-1 and (ꢀ), (+)-2] have been synthesized from the enantio-
meric chiro-inositols and evaluated as glycosidase inhibitors. Alternative syntheses of ido-tetrahydroxyazepanes (ꢀ)- and (+)-2
from myo-inositol were also developed. The key synthetic transformations were glycol fission and cyclization of the derived di-
aldehydes by double reductive amination. The d-manno-tetrahydroxyazepane [(ꢀ)-1] showed selective inhibition of a-l-fucosidase
and b-d-galactosidase, while the enantiomer [(+)-1] was a selective inhibitor of an a-d-galactosidase. In contrast, the l-ido-tetra-
hydroxyazepane (+)-2 was a broad spectrum hexosidase inhibitor, but showed none of the reported hexosaminidase inhibition. Its
enantiomer (ꢀ)-2 is a poor hexosidase inhibitor.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
for most alternative starting materials such as the hexo-
ses. Previously we reported the synthesis of the d-manno-
(ꢀ)-1 and l-manno-(+)-1 tetrahydroxyazepanes from
these starting materials,17 and now extend this approach
to the d- and l-ido-isomers (ꢀ)-2 and (+)-2. The inhibi-
tory properties of the four tetrahydroxyazepanes against
eight glycosidases are also reported.
Iminosugars, having nitrogen as the ring hetero-atom
instead of oxygen, and their derivatives have been
widely studied inhibitors of oligosaccharide processing
enzymes such as glycosidases and glycosyltransferases1,2
which are involved in the biosynthesis of the epitopes
responsible for various biological molecular recognition
events linked to diseases such as diabetes3 and cancer.4,5
Of the large number of such inhibitors developed, both
as molecular probes and potential therapeutic agents,2
five- and six-membered iminosugar derivatives, notably
the 1-deoxy analogues, have received most attention,
and relatively few reports have appeared on the inhibi-
tory activities of the seven-membered analogues.6ꢀ13
While the six-membered 1-deoxy-iminosugars are gen-
erally selective inhibitors of the enzymes that cleave the
pyranosyl glycosides with the same configurations,14,15
this correlation is less reliable for seven-membered ana-
logues which can be attributed, at least in part, to the
increased flexibility of polyhydroxylated azepanes.11
2. Results and discussion
In the previous study azepanes (ꢀ)-1 and (+)-1 were
synthesized from d- and l-chiro-inositol, respectively,17
by cis-a-diol protection, oxidative trans-diol fission,18
reductive amination of the dialdehyde formed to give
the azepane,19,20 and deprotection. In this way, d-chiro-
inositol was converted to (ꢀ)-1 via (+)-3, (ꢀ)-4 and
(ꢀ)-5 (Fig. 1).
We have been interested in the use of the enantiomeric
chiro-inositols as starting materials for the synthesis of
polyhydroxylated chiral compounds,16a because both
enantiomers are readily available, which is not the case
Preparation of the ido-configured azepanes (ꢀ)- and (+)-
2 utilizing similar methodology requires selective protec-
tion of the four equatorial hydroxyl groups of l- and
d-chiro-inositol, respectively. This was achieved by reac-
tion with butan-2,3-dione and trimethylorthoformate in
the presence of camphorsulfonic acid, a procedure
Keywords: Iminosugar; Glycosidase inhibition; Synthesis; Inositols.
* Corresponding author. Tel.:+64-4-931-3000; fax:+64-4-931-3055;
e-mail: g.painter@irl.cri.nz
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.10.003

226
G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
d-chiro-Inositol-based trans-diol (ꢀ)-6 consequently
had to be modified before it could be used for the pre-
paration of azepanes. By Mitsunobu epoxide forma-
tion23 it was converted into the myo-inositol derivative
(ꢀ)-7, epoxide ring opening with iodide ion gave (ꢀ)-8,
mesylation [to (ꢀ)-9] and reductive elimination led to
alkene (ꢀ)-10 which was cis-dihydroxylated. The epox-
ide opening step occurred with high selectivity to give
the diaxial product (ꢀ)-8 in keeping with the Furst
Plattner rule,24 and cis-dihydroxylation from either face
of symmetrical alkene (ꢀ)-10 gave the myo-inositol diol
(ꢀ)-11. Attempts to form the myo-inositol diol (ꢀ)-11
directly from its isomer (ꢀ)-6 by epimerization under
various Mitsunobu conditions led only to epoxide (ꢀ)-7,
and the dimesylate and the ditriflate of the diol gave only
small yields of the alkene (ꢀ)-10 under reductive elim-
ination conditions. Oxidative fission of the cis-diol (ꢀ)-11
proceeded readily to afford dialdehyde l-12 in near
quantitative yield, and reductive amination of this pro-
duct, followed by deprotection, afforded the previously
reported tetrahydroxyazepane (+)-2 (Scheme 1).7ꢀ12
Figure 1.
known to favor the protection of 1,2-diequatorial trans-
diols on six-membered rings,21 and the products were
used to give the ido-compounds 2 as illustrated for the
conversion of d-chiro-inositol to (+)-2 in Scheme 1.
Although the 1H NMR spectrum of the first inter-
mediate (ꢀ)-616b did not allow the conclusion that its
diol was diaxial, it is expected to be so given the pro-
pensity of the oxygen atoms of the dioxane rings to be
equatorial. Attempted oxidative fission of the presumed
trans-diaxial vicinal diol moiety of the diacetal (ꢀ)-6
with sodium periodate or lead tetraacetate under var-
ious reaction conditions failed. Since cleavage of vicinal
diols with periodate involves cyclic iodine-containing
intermediates which cannot be formed from trans-diols
locked in the diaxial orientation on six-membered rings,
such diols, for example methyl 4,6-O-benzylidene-a-d-
altropyranoside, are stable towards this reagent.22
The previously unreported d-ido-azepane (ꢀ)-2 was pre-
pared in similar manner starting from l-chiro-inositol.
The best method found for the production of alkene (+)-
10 was ‘one-pot’ triflation of iodo-alcohol (+)-8 followed
by reduction (Zn-dust, AcOH) (Scheme 2). In this way
the alkene (+)-10 was obtained from (+)-8 in 95% yield,
this approach representing a significant improvement
over the elimination process illustrated in Scheme 1.
An alternative synthesis of (+)-2 was developed from the
known tetra-O-benzyl-myo-inositol (ꢀ)-15.25 Oxidative
Scheme 1. Reagents and conditions: (a) butanedione, CH(OMe)3, H+, MeOH, reflux (80%); (b) Ph3P, DEAD, THF, 0 ꢁC (68%); (c) AlCl3, MeCN,
NaI, 0 ꢁC (95%); (d) MsCl, Et3N, CH2Cl2 (57%); (e) Zn dust, AcOH, DMF, 80 ꢁC (92%); (f) NaIO4, RuCl3, EtOAc, MeCN, H2O (98%);
(g) NaIO4, activated silica, CH2Cl2 (90–95%); (h) NaCNBH3, MeOH, (Ph)2CHNH2, 3 A sieves, 78 ꢁC–rt; (i) TFA, H2O; (j) H2, Pd(OH)2/C, MeOH
(h–j), 42%.

G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
227
Although short and efficient, this synthesis of (ꢀ)-
and/or (+)-2 requires the resolution of myo-inositol.
In our hands the literature procedure, conducted via
the camphor acetal,26,27 required the use of both
crystallization and chromatography to afford homo-
chiral material.
In vitro inhibition profiles of the tetrahydroxyazepanes
(ꢀ)-, (+)-1 and (ꢀ)-, (+)-2 were determined against
eight enzymes, a-l-naringinase being a 6-deoxy-a-l-
mannosidase (Table 1). Much the most active, but least
selective, isomer, the l-ido-compound (+)-2, gave
mainly analogous results to those already reported for
this inhibitor with a- and b-glucosidase, a-mannosi-
dase, a- and b-galactosidase and a-fucosidase.8,12
However, Wong et al. found that it also inhibited b-d-
N-acetylglucosaminidase8 which is contrary to the
result given in Table 1. In our hands azepane (+)-2
showed no inhibition of this enzyme (lit.8 Ki=22.7 mM).
Potent inhibitors of hexosaminidase most often but not
always,28 feature an acetamido-functional group, so it
was not surprising that (+)-2 did not inhibit b-N-
acetylglucosaminidase. As a positive control, the known
hexosaminidase inhibitor 2-acetamido-1,2-dideoxy-
nojirimycin29 was assayed against this enzyme and,
under the assay conditions used >99% inhibition was
observed, thus confirming the integrity of the inhibition
assay. The enantiomer (ꢀ)-2 was much less potent, but
showed some activity against all but one of the enzymes
tested. On the other hand, the d- and l-manno-enantio-
mers (ꢀ)- and (+)-1 were selective towards a-fucosidase
and a-galactosidase, respectively, while also inhibiting
b-galactosidase. (ꢀ)-1 Showed only minor inhibition
(28% at 1.67 mM, lit.8 Ki=4.6 mM) against b-d-N-
acetylglucosaminidase.
Scheme 2. (a) Tf2O, Py, DMF; (b) Zn, AcOH (95%).
fission with periodate afforded dialdehyde (+)-16 that
was subjected directly to reductive amination (Scheme
3). In this case, NaBH(OAc)3 and benzylamine proved
superior to NaCNBH3 for the latter process. The
pentabenzyl azepane (+)-17 was isolated in good yield
and was deprotected to give (+)-2 which displayed
1
identical H and 13C NMR spectra to those of the sam-
ple prepared according to Scheme 1. The azepane (ꢀ)-2
was synthesized by the same method from (+)-15.
Scheme 3. (a) NaI)O4/SiO2, CH2Cl2; (b) NaBH(OAc)3, BnNH2,
CH2Cl2, (a, b 86%); (c) H2, Pd(OH)2/C, MeOH/AcOH (trace) (92%).
Table 1. Glycosidase inhibition by tetrahydroxyazepanesa
Glycosidase
Inhibitor
(+)-2
(ꢀ)-2
(ꢀ)-1
(+)-1
a-d-Glucosidase
(from Bacillius stearothermophilus)
95
IC50=6 mM
2025
38
30
b-d-Glucosidase
(from sweet almonds)
98
IC50=10 mM
20N.I.
N. I.
b-d-N-Acetylglucosaminidase
(from jack beans)
N.I.b
28
69
5
a-d-Mannosidase
(from jack beans)
99
IC50=17 mM
85
IC50=165 mM
N.I.
20
IC50=695 mM
a-l-Naringinase
(from Penicillium decumbens)
84
39
81
34
5
a-d-Galactosidase
(from green coffee beans)
42
98
IC50=4 mM
Ki=4.9ꢂ1.5 mMc
94
b-d-Galactosidase
(from A. oryzae)
100
IC50=20 mM
79
IC50=335 mM
94
IC50=98 mM
IC50=95 mM
a-l-Fucosidase
(from bovine kidney)
78
15
97
IC50=9 mM
39
a Percent inhibition at inhibitor concentration of 1.67 mM.
b N.I., no inhibition.
c The Ki was also determined using the computer program Grafit (purchased from Erithacus Software) and gave Ki=3.0ꢂ0.5 mM.

228
G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
As might be expected, in some cases there is strong
correlation between the configurations of the inhibitors
and those of the substrates of the corresponding inhib-
ited enzymes, but the same does not apply in all instan-
ces. For example, there is complete correlation between
the configuration of (+)-1 and that at C-1–C-4 of the
a-d-galactopyranosides and, likewise, (ꢀ)-1 and the a-l-
fucopyranosides are stereochemically analogous. How-
ever, in the case of the d-ido-isomer (ꢀ)-2 correlation
with a-d-mannosides occurs at two contiguous chiral
centers only and with the b-galactosides at three con-
tiguous chiral centres and, surprisingly, since this isomer
and b-glucosides have the same configuration, there is
only mild inhibition of the b-glucosidase. The least
selective but potent inhibitor, (+)-2, has a contiguous
xylo-triol that also occurs in the glucosides and
b-galactosides and there is good inhibition of the
respective enzymes in all cases, but for the a-manno-
sides, only two centers are common to the glycosides
and the inhibitor (+)-2, yet there is good inhibition.
carried out on pre-coated 0.25 mm thick Merck 60 F254
silica gel plates. Visualization was by UV exposure, or
by thermal development after spraying with basic
potassium permanganate or ethanolic phosphomolybdic
acid. Flash chromatography was carried out using
Merck Kieselgel 60 (230–400 mesh) under air pressure.
4.1. (20R,30R)-1D-1,2-Anhydro-3,4:5,6-bis-O-(20,30 -di-
methoxybutane-20,30-diyl)-myo-inositol [(ꢀ)-7]
Diethyl azodicarboxylate (3.65 mL, 23.2 mmol) was
added dropwise over 3–4 min to a stirred solution of
diol (ꢀ)-6 (9.18 g, 22.5 mmol) and triphenylphosphine
(6.00 g, 22.9 mmol) in anhydrous THF (75 mL) cooled
to 0 ꢁC under argon. After 90min stirring at 0C the
reaction mixture was concentrated in vacuo to 10% of
the original volume and diluted with ether (200 mL).
The ether phase was washed with HCl (120mL, 2M)
and the aqueous phase was extracted with ether (2Â150
mL). The combined ethereal extracts were washed with
aqueous NaHCO3 (200 mL, saturated) and dried
(MgSO4). After filtration, the solvent was removed in
vacuo and the product was purified by flash chromato-
graphy. Elution with EtOAc/light petroleum (1:3)
3. Conclusion
Concise syntheses, from inositols, of the tetra-
hydroxyazepanes (ꢀ)-, (+)-1 and (ꢀ)-, (+)-2 have been
developed. The l-manno-compound (+)-1 is a novel
selective inhibitor of a-d-galactosidase, while the (ꢀ)-1
enantiomer inhibits a-l-fucosidase selectively. Less selec-
tivity is shown by the ido-isomers (2), but the (+)-isomer
is active against several enzymes. There is some corre-
lation between the configurations of the inhibitors and
those of the substrates of the enzymes inhibited. Surpris-
ingly, however, (ꢀ)-2 only inhibits b-glucosidase very
poorly. Some of the apparent anomalies may be explained
by the extra flexibility of tetrahydroxyazepanes11 as com-
pared with pyranoses.
afforded (ꢀ)-7 as a white solid (5.94 g, 15.2 mmol,
20
D
68%); mp 73–75 ꢁC; ½aŠ ꢀ232 (c 0.92, CDCl3); 1H
NMR d 4.10–4.05 (1H, m), 3.95–3.89 (1H, m), 3.69–3.58
(2H, m), 3.30–3.25 (1H, m), 3.29 (3H, s), 3.28 (3H, s),
3.26 (3H, s), 3.24 (3H, s), 3.13 (1H, d, J 3.8), 1.34 (3H,
s), 1.32 (3H, s), 1.29 (3H, s), 1.28 (3H, s); 13C
NMR101.1 (C), 100.8 (C), 100.0 (C), 99.8 (C), 70.8
(CH), 69.0(CH), 68.6 (CH), 64.6 (CH), 54.4 (CH), 53.2
(CH), 48.5 (CH3), 48.4 (CH3), 48.2 (CH3), 18.0(3)
(CH3), 17.9(7) (CH3); m/z (FAB, DCM/NBA) 389
[(MꢀH)+, 2%], 359 (100), 327 (10), 209 (5); HRMS m/z
calcd for C18H30O9 (M)+ 390.1890, found 390.1898.
4.2. (20R,30R)-1D-1-Deoxy-1-iodo-2,3:4,5-bis-O-(20,30-di-
methoxybutane-20,30-diyl)-chiro-inositol [(ꢀ)-8]
4. Experimental
Aluminum trichloride (2.61 g, 19.6 mmol) was added in
portions to a stirred solution of the epoxide (ꢀ)-7 (5.94
g, 15.2 mmol) and sodium iodide (6.10g, 40.7 mmol) in
anhydrous MeCN (120mL) at 0 ꢁC under argon. After
20min stirring at 0 ꢁC the reaction mixture was con-
centrated in vacuo and the residue was taken up in ether
(200 mL). The ether phase was washed with water (150
mL) and the aqueous phase extracted with further ether
(2Â150mL). The combined ethereal extracts were
washed with aqueous NaHCO3 (200 mL, saturated)
then with aqueous Na2S2O3 (2Â150mL, saturated) and
dried (MgSO4). After filtration, the solvent was
removed in vacuo and the residue purified by flash
chromatography. Elution with EtOAc/light petroleum
(1:4–1:1.5) afforded iodo alcohol (ꢀ)-8 as a white solid
d-chiro-Inositol and l-chiro-inositol were prepared by
demethylation30 of pinitol (New Zealand Pharmceu-
ticals Ltd) and quebrachitol (Rubber Research Institute
of Malaysia), respectively. 1H and 13C NMR spectra were
recorded on a Bruker WM-300 spectrometer at 300 and
75MHz, respectively, using deuteriochloroform as solvent
(unless otherwise stated) and tetramethylsilane as internal
standard unless otherwise indicated. In the 13C spectra the
numbers of attached protons were determined by DEPT
experiments. Mass spectra were recorded at the Mass
Spectrometry Unit, Hort. Research, Palmerston North,
New Zealand on a VG70-250S double focusing, mag-
netic sector mass spectrometer under chemical ionization
conditions using isobutene or ammonia as the ionizing
gas, or under high-resolution FAB conditions in a gly-
cerol or nitrobenzyl alcohol matrix. Microanalyses were
carried out by the Campbell Microanalytical Labora-
tory, University of Otago. Melting points were deter-
mined using a Buchi 510melting point apparatus and
are uncorrected. Optical rotations were measured using
a Perkin-Elmer 241 polarimeter, in a 1 dm path length
cell. Analytical thin layer chromatography (TLC) was
(7.48 g, 14.4 mmol, 95%). Crystallization from EtOH–
20
H2O gave white prisms; mp 178–179 ꢁC; ½aŠ ꢀ161 (c
D
0.90, CHCl3); 1H NMR d 4.39 (1H, dd, J=9.8, 2.8 Hz),
4.31 (1H, dd, J=4.0, 3.1 Hz), 4.22 (1H, bt, J=2.7 Hz),
4.05 (1H, t, J=10.0 Hz), 3.94 (1H, t, J=9.6 Hz), 3.34
(1H, dd, J=9.2, 4.2 Hz), 3.28 (3H, s), 3.28 (3H, s), 3.26
(3H, s), 3.24 (3H, s), 2.85 (1H, bs), 1.31 (3H, s), 1.30
(3H, s), 1.28 (3H, s), 1.26 (3H, s); 13C NMR d 100.8 (C),

G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
229
100.6 (C), 99.4 (C), 99.1 (C), 74.1 (CH), 69.4 (CH), 68.4
(CH), 67.1 (CH), 66.1 (CH), 48.5 (CH3), 48.4 (CH3), 48.3
4.5. (20R,30R)-1D-3,4:5,6-Bis-O-(20,30 -dimethoxybutane-
20,30-diyl)-myo-inositol [(ꢀ)-11]
(CH3), 29.3 (CH), 18.1 (CH3), 18.0(CH ); m/z (FAB,
3
NBA) 519 [(M+H)+, 1%], 517 (1), 503 (2), 487 (20), 101
(100); HRMS m/z calcd for C18H30IO9 (M-H)+ 517.0935,
found 517.0943. Anal. calcd for C18H31IO9: C, 41.71; H,
6.03; I, 24.48. Found: C, 41.8; H, 6.0; I, 24.5.
Alkene (ꢀ)-10 (138 mg, 0.369 mmol) in EtOAc (3 mL)
was added to a stirred solution of NaIO4 (88.0mg,
0.411 mmol) in H2O (1 mL) and MeCN (3 mL). To this
mixture was added RuCl3 (10.0 mg, 48.2 mmol). The
reaction mixture was stirred for 10min and aqueous
Na2S2O3 (10mL, saturated) was added and the stirring
was continued for a further 15 min. The reaction mix-
ture was extracted with ether (3Â30mL) and the com-
bined ethereal extracts were dried (MgSO4). After
4.3. (20R,30R)-1D-1-Deoxy-1-iodo-6-O-methanesulfonyl-
2,3:4,5-bis-O-(20,30-dimethoxybutane-20,30-diyl)-chiro-in-
ositol [(ꢀ)-9]
Triethylamine (15.0mL, 108 mmol) was added drop-
wise to a stirred solution of iodo alcohol (ꢀ)-8 (5.66 g,
10.9 mmol) and methanesulphonyl chloride (2.53 mL,
filtration, the solvent was removed in vacuo to give diol
(ꢀ)-11 as a syrup (147 mg, 0.360 mmol, 98%), ½aŠ
22
D
1
ꢀ246 (c 0.52, CHCl3); H NMR d 4.11 (1H, t, J=2.8
ꢁ
32.7 mmol) in CH2Cl2 (30mL) at 0 C under argon. The
Hz), 4.06 (1H, t, J=10.0 Hz), 3.92 (1H, t, J=9.9 Hz),
3.65 (1H, dd, J=9.7, 2.9 Hz), 3.61 (1H, t, J=9.9 Hz),
3.52 (1H, dd, J=9.9, 2.6 Hz), 3.28 (3H, s), 3.27 (6H, s),
3.23 (3H, s), 2.68 (1H, bs), 2.46 (1H, bs), 1.33 (3H, s),
1.32 (3H, s), 1.30(3H, s), 1.28 (3H, s); 13C NMR d 100.6
(C), 100.0 (C), 99.5 (C), 99.3 (C), 70.7 (CH), 70.4 (CH),
70.3 (CH), 69.4 (CH), 68.3 (CH), 66.0 (CH), 48.4 (CH3),
ice bath was removed and the reaction mixture was
stirred at rt for 14 h. It was diluted with CH2Cl2 (120
mL) and washed with HCl (100 mL, 2M), and the aqu-
eous phase was extracted with further CH2Cl2 (100 mL).
The combined organic extract was washed with brine
(150mL) and dried (MgSO ). After filtration, the sol-
4
vent was removed in vacuo and the product was purified
by flash chromatography. Elution with EtOAc/light
petroleum (1:9–1:1) afforded alkene (ꢀ)-10 as a colour-
less oil (469 mg, 1.25 mmol, 11%) followed by the iodo
48.3 (CH3), 48.2 (CH3), 18.1 (CH3), 18.0(CH ); m/z
3
(EI) 377 [(M-OCH3)+, 5%], 112 (100), 101 (80); HRMS
(EI) m/z calcd for C17H29O10 (M-Me)+ 393.1761, found
393.1768.
mesylate (ꢀ)-9 as a colourless oil (3.70g, 6.20mmol,
25
D
57%), ½aŠ ꢀ153 (c 0.50, CHCl3); 1H NMR d 5.03 (1H,
4.6. (20R,30R)-2,3:4,5-Bis-O-(20,30-dimethoxybutane-20,30-
diyl)-L-ido-hexodialdose [L-12]
t, J=2.9 Hz), 4.61 (1H, dd, J=9.9, 2.7 Hz), 4.35 (1H,
dd, J=4.2, 3.3 Hz), 4.03 (1H, t, J=9.9 Hz), 3.92 (1H, t,
J=9.4 Hz), 3.29 (3H, s), 3.28 (3H, s), 3.26 (3H, s), 3.24
(4H, bs+), 3.14 (3H, s), 1.31 (3H, s), 1.29 (3H, s), 1.28
(3H, s), 1.27 (3H, s); 13C NMR d 100.8 (C), 99.3 (C),
82.4 (CH), 69.1 (CH), 66.9 (CH), 66.4 (CH), 65.9 (CH),
48.6 (CH3), 48.5 (CH3), 39.4 (CH3), 25.7 (CHI), 18.0
(CH3), 17.9 (CH3); m/z (FAB, NBA) 595 [(M-H)+,
5%], 581 (10), 575 (5), 565 (30), 173 (20), 115 (60), 101
(100); HRMS m/z calcd for C19H33IO11S (M)+
596.0788, found 596.0802.
A solution of the diol (ꢀ)-11 (147 mg, 0.360 mmol) in
CH2Cl2 (5 mL) was added to a stirred suspension of
NaIO4 (0.30 g, 1.6 mmol) adsorbed on silica gel
(1.15g).18 The suspension was stirred at rt for 14 h and
filtered through a pad of silica. The solids were washed
with EtOAc (25 mL) and the solvents removed in vacuo
to give essentially pure syrupy dialdehyde l-12 (140mg,
0.341 mmol, 95%). A sample of the dialdehyde was
dried by heating in refluxing C6D6 under argon in a
Dean Stark apparatus for 20min. 1H NMR d (C6D6)
9.62 (2H, d, J=1.5 Hz), 4.78 (2H, d, J=9.7 Hz), 4.57
(2H, d, J=9.7 Hz), 3.32 (6H, s), 3.11 (6H, s), 1.40(6H,
s), 1.34 (6H, s); 13C NMR d (C6D6) 198.4 (CH), 98.0
(C), 97.9 (C), 70.7 (CH), 63.8 (CH), 47.4 (CH3), 46.6
(CH3), 16.5 (CH3), 16.4 (CH3); m/z (FAB, NBA/DCM)
375 [(MꢀOCH3)+, 5%], 343 (8), 243 (5), 116 (30), 101
(100), 73 (20). HRMS m/z calcd for C18H31O10
(M+H)+ 407.1917, found 407.1934.
4.4. (2S,3R,4R,5S,20R,30R) - 2,3:4,5 - Bis - O - (20,30 - di-
methoxybutane-20,30-dioxy)-cyclohexene [(ꢀ)-10]
Anhydrous DMF (20mL) was cannulated onto a mix-
ture of the iodo mesylate (ꢀ)-9 (3.70g, 6.20mmol) and
zinc dust (1.31 g, 20.0 mmol) under argon. The suspen-
sion was heated with stirring to 80 ꢁC and acetic acid (10
mL) was injected. After being stirred at this temperature
for 40min the reaction mixture was cooled to rt and
filtered through Celite which was washed with ether
(3Â100 mL) and the combined filtrate and washings
were concentrated in vacuo. The residue was purified by
flash chromatography and elution with EtOAc/light pet-
4.7. (3S,4R,5R,6S,20R,30R)-N-(Diphenyl)methyl-3,4:5,6-
bis-O-(20,30-dimethoxybutane-20,30-dioxy)-azepane [(ꢀ)-13]
Acetic acid (40 mL, 0.67 mmol) was injected into a stir-
red mixture of the dialdehyde (140mg, 0.329 mmol),
sodium cyanoborohydride (60mg, 0.96 mmol) and oven
dried 3 A molecular sieves (0.60 g) in MeOH (25 mL) at
ꢀ78 ꢁC under argon. (Diphenylmethyl)amine (50 mL,
0.29 mmol) was added dropwise to over 10 min. The
cold bath was removed and the reaction mixture stirred
at rt for 17 h, then filtered through Celite and the Celite
was washed with EtOAc (2Â50mL). The combined fil-
trate and washings were taken to dryness in vacuo and
the remaining residue was taken up in diethyl ether (100
roleum (1:9–1:3) afforded the alkene (ꢀ)-10 as a thick
25
gum (2.13 g, 5.70mmol, 92%), ½aŠ ꢀ164 (c 0.76,
D
1
CHCl3); H NMR d 5.56 (2H, bs), 4.45–4.40(2H, m),
3.95–3.90(2H, m), 3.29 (6H, s), 3.24 (6H, s), 1.31 (12H,
bs); 13C NMR d 127.6 (CH), 100.9 (C), 100.2 (C), 70.5
(CH), 68.8 (CH), 48.5 (CH3), 48.1 (CH3), 18.2 (CH3), 18.1
(CH3); m/z (FAB, NBA/DCM) 373 [(M-H)+, 1%], 343
(5), 211 (5), 116 (20), 101 (100); HRMS m/z calcd for
C18H29O8 (MꢀH)+ 373.1862, found 373.1844. Anal. calcd
for C18H30O8: C, 57.74; H, 8.0 8. Found: C, 57.6; H, 7.8.

230
G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
mL) and washed with aqueous NaHCO3 (80mL, satu-
rated). The aqueous phase was extracted with diethyl
ether (2Â50mL) and the combined organic phases were
washed with brine (100 mL) and dried (MgSO4). After
filtration, the solvent was removed in vacuo to give the
crude product (175 mg) which was purified by flash
chromatography. Elution with CH2Cl2 then EtOAc in
CH2Cl2 (1:9) afforded the azepane derivative (ꢀ)-13 as a
solid (20mg, 0.12 mmol, 92%), ½aŠ20+6.3 (c 0.40, H2O,
D
1
HCl salt); H NMR d (D2O/DCl) 3.99–3.90(2H, m),
3.59–3.54 (2H, m), 3.23 (2H, dd, J=13.8, 2.1 Hz), 3.08
(2H, dd, J=13.8, 8.1 Hz); 13C NMR d (D2O/DCl) 76.9
(CH), 67.8 (CH), 47.1 (CH2); m/z (FAB, glycerol/H2O)
164 [(M+H)+, 100%], 115 (30). HRMS m/z calcd for
C6H14NO4 (M+H)+ 164.0923, found 164.0940.
19
D
colourless oil (110 mg, 0.197 mmol, 60%), ½aŠ ꢀ187 (c
The following compounds were made from 1l-chiro-
inositol by the methods described above for their enan-
tiomers, NMR data obtained was essentially identical to
that reported for their enantiomers.
1
0.48, CHCl3); H NMR d 7.38–7.34 (4H, m), 7.30–7.20
(4H, m), 7.19–7.12 (2H, m), 4.66 (1H, s), 3.88–3.80(2H,
m), 3.72–3.66 (2H, m), 3.26 (6H, s), 3.21 (6H, s), 2.82
(2H, dd, J=13.5, 2.0Hz), 2.62 (2H, dd, J=13.5, 9.5 Hz),
1.25 (6H, s), 1.18 (6H, s); 13C NMR d 142.9 (C), 142.4
(C), 129.0(CH), 128.9 (CH), 128.5 (CH), 128.4(5) (CH),
127.5 (CH), 99.5 (C), 98.6 (C), 75.5 (CH), 73.6 (CH), 66.0
(CH), 53.1 (CH2), 48.4 (CH3), 48.1 (CH3), 17.9 (CH3); m/
z (FAB, NBA/DCM) 556 [(MꢀH)+, 10%], 167 (100),
116 (15), 101 (10). HRMS m/z calcd for C31H43NO8
(M)+ 557.2987, found 557.2993.
4.10. (20S,30S)-1L-2,3:4,5-Bis-O-(20,30-dimethoxybutane-
20,30-diyl)-chiro-inositol [(+)-6]16a
20
Pale brown foam, ½aŠ +184 (c 1.50, CDCl3); m/z
D
(FAB, DCM/NBA) 409 [(M+H)+, 1%], 407 (2), 393
(2), 377 (25), 101 (100); HRMS m/z calcd for C18H31O10
(MꢀH)+ 407.1917, found 407.1886.
4.8. (3S,4R,5R,6S) - N - Diphenylmethyl - 3,4,5,6 - tetra-
hydroxyazepane [(+)-14]
4.11. (20S,30S)-1L-1,2-Anhydro-3,4:5,6-bis-O-(20,30 -di-
methoxybutane-20,30-diyl)-myo-inositol [(+)-7]
20
D
HRMS (FAB, DCM/NBA) m/z calcd for C18H29O9
Water (0.1 mL) was added dropwise to a stirred solu-
tion of the azepane derivative (ꢀ)-13 (110mg, 0.197
mmol) in TFA (2.5 mL). After the solution had been
stirred for 12 h at rt the solvents were removed in vacuo
and the residue was taken up in ether (50mL) and
aqueous NaOH (30mL, 0.5 M). The aqueous phase was
extracted with further ether (2Â30mL) and the com-
bined ethereal solutions were dried (MgSO4). After fil-
tration, the solvent was removed in vacuo. The product
was purified by flash chromatography. Elution with
EtOAc then MeOH–EtOAc (1:40) afforded the N-pro-
White solid, mp 74–75 ꢁC; ½aŠ +221 (c 1.41, CDCl3);
(MꢀH)+ 389.1812, found 389.1815.
4.12. (20S,30S)-1L-6-Deoxy-6-iodo-2,3:4,5-bis-O-(20,30-di-
methoxybutane-20,30-diyl)-chiro-inositol [(+)-8]
[a]2D1+178 (c 2.22, CHCl3); m/z (FAB, NBA/MeOH)
517 [(MꢀH)+, 1%], 503 (2), 487 (30), 337 (5), 211 (7),
115 (30), 101 (100), 73 (25); HRMS m/z calcd for
C18H31IO9 (M)+ 518.1013, found 518.0968.
tected tetrahydroxyazepane (+)-14 as a white solid
22
D
(49.0mg, 0.149 mmol, 76%), mp 91–92 ꢁC; ½aŠ +55 (c
4.13. (2R,3S,4S,5R,20S,30S) - 2,3:4,5 - Bis - O - (20,30 - di-
methoxybutane-20,30-dioxy)-cyclohexene [(+)-10]
1
0.22, CD3OD); H NMR (CD3OD) d 7.39–7.10(10H,
m), 4.64 (1H, s), 3.58 (4H, bs), 2.91–2.78 (2H, m), 2.59–
2.47 (2H, m); 13C NMR d (CD3OD) 142.5 (C), 142.4
(C), 129.0(CH), 128.5 (CH), 128.4 (CH), 127.7 (CH),
76.3 (CH), 75.8 (CH), 73.2 (CH), 57.9 (CH2); m/z (FAB,
glycerol/H2O, ) 330[M+H] +, 30%], 167 (100). HRMS
m/z calcd for C19H24NO4 (M+H)+ 330.1705, found
330.1735. Anal. calcd for C19H23NO4: C, 69.28; H, 7.04;
N, 4.25. Found: C, 69.3; H, 7.0; N, 4.2.
Pyridine (0.820 mL, 10.1 mmol) was added dropwise to
a stirred solution of (+)-8 (2.02 g, 3.90 mmol) and triflic
anhydride (0.920 mL, 5.47 mmol) in anhydrous DMF
(50mL) at 0 ꢁC under argon. The cold bath was
removed and after the solution had been stirred at rt
for 90min Zn-dust (420mg, 6.32 mmol) and acetic
acid (6 mL) were added and the stirring was con-
tinued for 10h. After the addition of aqueous
NaHCO3 (120mL, saturated) the reaction mixture
was extracted with ether (3Â100 mL) and the com-
bined ethereal extracts were washed with H2O (5Â80
mL). After being dried (MgSO4) and filtered, the sol-
4.9. (3S,4R,5R,6S)-3,4,5,6-Tetrahydroxyazepane [(+)-2]
Palladium hydroxide on carbon (20% Pd, 32 mg) was
added to a stirred solution of the N-protected tetra-
hydroxyazepane (+)-14 (43 mg, 0.13 mmol) in MeOH
(5 mL). The reaction atmosphere was changed to
hydrogen and the mixture was stirred for 14 h. The
hydrogen was removed and the suspension was filtered
through Celite. The Celite was washed with MeOH and
then water, the combined filtrate and washings were
concentrated in vacuo and the residue was partitioned
between H2O (10mL) and light petroleum (10mL). The
aqueous phase was washed with a further portion of
light petroleum (10mL), separated and centrifuged
(1500 rpm 15 min). The supernatant was then con-
centrated in vacuo to give (+)-2 as a low melting yellow
vent was removed in vacuo to give essentially pure
20
D
(+)-10 as a thick gum (1.39 g, 3.72 mmol, 95%), ½aŠ
+175 (c 1.50, CHCl3); m/z (FAB, NBA/MeOH) 373
[(M-H)+, 1%], 343 (10), 211 (4), 116 (20), 101 (100),
78 (25); HRMS m/z calcd for C18H29O8 (MꢀH)+
373.1862, found 373.1848.
4.14. (20S,30S)-1L-3,4:5,6-Bis-O-(20,30-dimethoxybutane-
20,30-diyl)-myo-inositol [(+)-11]
22
½aŠ +232 (c 0.64, CHCl3); m/z (FAB, NBA/MeOH)
D
431 [(M+Na)+, 3%), 407 (1), 393 (3), 377 (60), 345 (5),

G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
231
313 (8), 116 (20), 101 (100), 73 (20); HRMS m/z calcd
for C18H31O10 (MꢀH)+ 407.1917, found 407.1897.
(C), 139.1 (C), 129.4 (CH), 128.6 (CH), 128.0(2 lines,
CH), 127.7 (CH), 127.4 (CH), 84.1 (CH), 80.2 (CH),
74.2 (CH), 72.3 (CH), 63.2 (CH), 54.8 (CH); m/z (FAB,
NBA/DCM) 614 [(M+H)+, 100%], 506 (10) 391 (9)
149(13) 91 (60). HRMS m/z calcd for C41H44NO4
(M+H)+ 614.3270, found 614.3290.
4.15. (20S,30S) - 2,3:4,5 - Bis - O - (20,30 - dimethoxybutane -
20,30-diyl)-D-ido-hexodialdose [D-12]
Syrup, m/z (FAB, NBA/MeOH) 375 [(MꢀOCH3)+,
5%)], 343 (7), 243 (5), 116 (20), 101 (100), 73 (20);
HRMS m/z calcd for C18H31O10 (M+H)+ 407.1917,
found 407.1931.
4.20. 2,3,4,5-Tetra-O-benzyl-L-ido-hexodialdose [(ꢀ)-16]
22
1
½aŠD ꢀ15.7 (c=0.64, CHCl3); H NMR d 9.66 (2H, s),
7.33–7.21. (20H, m), 4.75 (2H, d, J=12 Hz) 4.56 (2H, d
J=12 Hz), 4.38 (4H, d, J=12 Hz) 4.03 (2H, d, J=6 Hz)
3.69 (2H, d, J=6 Hz); 13C NMR d 200.4 (2ÂC¼O)
137.6 (C) 137.5 (C) 129.0(CH) 128.9 (CH); 128.9 (CH),
128.5 (CH), 128.5 (CH),80.8 (CH), 78.8 (CH),74.3 (CH)
73.3 (CH); m/z (FAB, NBA/DCM) 539 [M+H]+, 1%],
181 (21) 91 (100); HRMS m/z calcd for C34H35O6
(M+H)+ 539.2434, found 539.2419.
4.16. (3R,4S,5S,6R,20S,30S)-N-Diphenylmethyl-3,4:5,6-bis-
O-(20,30-dimethoxybutane-20,30-dioxy)-azepane [(+)-13]
22
Syrup, ½aŠ +191 (c 0.84, CHCl3); m/z (FAB, NBA/
D
MeOH) 556 [(MꢀH)+, 5%], 526 (3), 167 (100), 116
(10), 101 (5); HRMS m/z calcd for C31H43NO8 (M)+
557.2987, found 557.2995.
4.17. (3R,4S,5S,6R) - N - Diphenylmethyl - 3,4,5,6 - tetra-
hydroxyazepane [(ꢀ)-14]
4.21.
(3R,4S,5S,6R)-N-Benzyl-3,4,5,6-tetra-O-benzyl-
azepane [(ꢀ)-17]
22
White solid; mp 89–90 ꢁC; [a]D20ꢀ62 (c 0.20, CD3OD);
m/z (FAB, glycerol–H2O) 330[(M+H) +, 60%], 167
(100); HRMS m/z calcd for C19H24NO4 (M+H)+
330.1705, found 330.1699.
½aŠ ꢀ15.9 (c 3.3, CDCl3), m/z (FAB, NBA/DCM) 614
D
[(M+H)+, 100%], 506 (9) 391 (19) 149 (59) 55 (83);
HRMS m/z calcd for C41H44NO4 (M+H)+ 614.3270,
found 614.3252.
4.18. (3R,4S,5S,6R)-3,4,5,6-Tetrahydroxyazepane [(ꢀ)-2]
4.22. (3S,4R,5R,6S)-3,4,5,6-Tetrahydroxyazepane [(+)-2]
20
Low melting yellow solid, ½aŠ ꢀ6.5 (c 0.40, H2O, HCl
Pd(OH)2 on carbon (650mg) was added to a solution of
(+)-17 (113 mg, 0.184 mmol) and acetic acid (5 mL, 0.08
mmol) in MeOH (7 mL). Hydrogen was introduced (to
200 psi) and the mixture was stirred for 72 h. After
removal of the hydrogen the mixture was filtered
through Celite. The pad was washed with MeOH (30
D
salt); m/z (FAB, glycerol–H2O) 164 [(M+H)+, 100%];
HRMS m/z calcd for C6H14NO4 (M+H)+ 164.0923,
found 164.0917.
4.19. (3S,4R,5R,6S)-N-Benzyl-3,4,5,6-tetra-O-benzyl-
azepane [(+)-17]
mL) and the solvent and washings were concentrated in
22
D
vacuo to give (+)-2 (17 mg, 0.104 mmol, 57%); ½aŠ
A solution of the diol (ꢀ)-1525 (100 mg, 0.185 mmol) in
CH2Cl2 (2.5 mL) was added to a stirred suspension of
NaIO4 (0.318 g, 1.66 mmol) absorbed on silica (1.18 g)
in CH2Cl2 (2.5 mL). The suspension was stirred at rt for
3.5 h, filtered and the residue was washed with EtOAc
+9.8 (c 0.65, D2O); m/z (FAB, glycerol–MeOH) 164
[(M+H)+, 15%], 146 (12) 115 (16); HRMS m/z calcd
for C6H14NO4 (M+H)+ 164.0902, found 164.0923.
4.23. Glycosidase assay conditions
(10mL) and then with CH Cl2 (10mL). The solvents
2
were removed in vacuo to give dialdehyde (+)-16 (99
mg, 0.18 mmol, 99%). Triacetoxyborohydride (114 mg,
0.538 mmol) was added to a stirred solution of this dia-
ldehyde and benzylamine (24.0 mL, 0.216 mmol) in
CH2ClCH2Cl (5 mL) under argon. After stirring the
mixture at rt for 18 h NaHCO3 (500 mg) was added and
the reaction mixture was concentrated in vacuo. The
residue was partitioned between EtOAc (50mL) and
H2O (30mL). The aqueous phase was re-extracted with
EtOAc (50mL) and the combined organic extracts were
washed with aqueous NaHCO3 (30mL, saturated) and
All inhibition assays were performed in 0.1 M HEPES
buffer at 37 ꢁC and pH 6.8. The amount of enzyme used
varied from 0.01 to 0.05 units in a total volume of 300
mL. The concentration of the p-nitrophenyl glycosides
used as substrates was 500 mM for % inhibition and IC50
determinations. Values in Table 1 were determined at an
inhibitor concentration of 1.67 mM. The optical absor-
bance was measured at 410nm after a 5-min incubation
time. Assays were quenched by the addition of sodium
borate buffer at pH 9.8 (100 mL). For Ki determinations,
substrate concentrations ranged from 0.25 to 6.00 mM
and inhibitor concentrations ranged from 2.1 to 33 mM.
brine (30mL). After drying of the solution (MgSO )
4
and filtration, the filtrate was taken to dryness in vacuo
to give the crude product which was purified by flash
chromatography. Elution with EtOAc/light petroleum
Acknowledgements
(1:20–1:9) afforded (+)-17 [113 mg, 0.184 mmol, 99%
22
D
from (ꢀ)-15] as a clear oil; ½aŠ +15.3 (c 2.22, CHCl3);
The authors thank Dr Herbert Wong for an excellent
NMR service, Dr J. B. Hart and Dr J. A. Gerrard for help
with the glycosidase assays, Prof George Fleet for
insightful ideas and the Foundation for Research, Science
1H NMR d 7.44–7.07 (20H, m), 4.60 (4H, q, J=11.4,
5.1 Hz), 4.45 (4H, q, J=12.0, 12.6 Hz) 3.76 (4H, s) 3.61
(2H, s) 2.77–2.63 (4H, m); 13C NMR d 139.5 (C), 139.2

232
G. F. Painter et al. / Bioorg. Med. Chem. 12 (2004) 225–232
and Technology for financial support (Science and Tech-
nology Post-Doctoral Fellowship, contract #C08821 to
G.F.P. and Public Good Science Fund, contract
#C08811-D, to A.F.). Prof Robin Ferrier assisted with
the preparation of the manuscript.
Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F.
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