in good yield. Proton and carbon NMR spectra of the free
amine (Ϫ)-1 recorded in D2O were more complex than
expected. In light of this result, to further characterise (Ϫ)-1 a
small sample was per-acetylated and pentaacetyl compound
(Ϫ)-8 was isolated without incident. It was subsequently estab-
lished that the expected NMR spectra for (Ϫ)-1 could be
obtained by recording the sample in 20% DCl–D2O or 40%
NaOD–D2O.
(110 mL) was added and to this stirred mixture was added
a solution of 1,2:5,6-di-O-isopropylidene-1-chiro-inositol 4
(4.69 g, 18.0 mmol) in CH2Cl2 (110 mL). The reaction mixture
was stirred at RT for 80 min, then filtered and washed with
CH2Cl2. The combined supernatant was concentrated in vacuo.
The solid was crystallised from ethyl acetate to give (Ϫ)-5 (4.00
g, 86%) as a white solid (Found: C, 55.6; H, 7.2. Calc. for
C12H18O6: C, 55.80; H, 7.03%); mp 141–142 ЊC; [α]D20 Ϫ57 (c 1.6,
CHCl3); νmax (CDCl3)/cmϪ1 2992, 2939, 1731, 1383, 1249, 1213,
1074; δH 9.66 (2H, s), 4.55 (2H, s), 4.53 (2H, s), 1.58 (6H, s),
1.35 (6H, s); δC 202.0 (CH), 111.8 (C), 80.8 (CH), 76.4 (CH),
26.9 (CH3), 25.4 (CH3).
Synthesis of the previously unreported azepane, (3S,4S,5S,
6S)-3,4,5,6-tetrahydroxyazepane (ϩ)-1, was achieved by the
same route but starting from -chiro-inositol (Scheme 2).
(3R,4R,5R,6R)-N-Benzhydryl-3,4:5,6-bis(isopropylidene-
dioxy)azepane (؊)-6
Acetic acid (2.16 mL, 35.5 mmol) was injected into a stirred
mixture of the dialdehyde (Ϫ)-5 (4.68 g, 18.1 mmol), sodium
cyanoborohydride (2.49 g, 39.6 mmol) and oven-dried 3 Å
molecular sieves (2.90 g) in anhydrous MeOH (300 mL) under
argon cooled to Ϫ78 ЊC. Benzhydrylamine (2.83 mL, 16.4
mmol) was then added dropwise to the reaction mixture over a
period of 60 min in 6 aliquots. The stirred reaction mixture was
warmed to ambient temperature over a period of 15 h. The
reaction mixture was filtered through Celite and the Celite
washed with ethyl acetate (2 × 200 mL). The combined solvent
was then removed in vacuo, the remaining residue was taken up
in diethyl ether (150 mL), and the extract washed with saturated
aq. sodium hydrogen carbonate (80 mL). The aqueous phase
was back-extracted with diethyl ether (2 × 100 mL) and the
combined organic extract was washed with brine (150 mL)
and dried (MgSO4). After filtration the solvent was removed
in vacuo to give the crude material (6.5 g). Silica gel chrom-
atography and elution with 50–67–100% CH2Cl2 in petroleum
spirit, then 10% ethyl acetate in CH2Cl2, afforded the azepane
(Ϫ)-6 (5.28 g, 12.9 mmol, 71%) as a white solid (Found: C, 73.5;
H, 7.8; N, 3.4. C25H31NO4 requires C, 73.3; H, 7.63; N, 3.42%);
mp 168 ЊC; [α]D22 Ϫ6.8 (c 3.0, CHCl3); νmax (CDCl3)/cmϪ1 3086,
3064, 3028, 2990, 2938, 2824, 1952, 1898, 1809, 1600, 1492,
1455, 1386, 1260, 1212, 1160, 1047; δH 7.45–7.36 (4H, m), 7.30–
7.22 (4H, m), 7.20–7.13 (2H, m), 4.76 (1H, s), 4.42–4.33 (2H,
m), 4.26–4.19 (2H, m), 3.15 (2H, dd, J 13.3, 2.8), 2.50 (2H, dd,
J 13.3, 11.4), 1.45 (6H, s), 1.33 (6H, s); δC 142.7 (C), 142.6 (C),
129.2 (CH), 129.1 (CH), 128.2 (CH), 128.1 (CH), 127.7 (CH),
108.7 (C), 79.1 (CH), 74.0 (CH), 72.7 (CH), 50.5 (CH2), 27.4
(CH3), 24.3 (CH3).
Scheme 2 Reagents and conditions: (i)–(iv) as for Scheme 1.
In summary we have demonstrated the expedient synthesis of
the tetrahydroxyazepanes (ϩ)-1 and (Ϫ)-1 by a novel route
from chiro-inositols. Access to both enantiomers should allow
some insight into the specificity of tetrahydroxyazepanes as
glycosidase inhibitors.
Experimental
1-chiro-Inositol was prepared on 50–100 g scale by the
demethylation18 of pinitol which was purchased from New
Zealand Pharmaceuticals Ltd. 1-chiro-Inositol was similarly
prepared from quebrachitol which was purchased from the
Rubber Research Institute of Malaysia. NMR spectra were
1
recorded on a Bruker WM-300 instrument (300 MHz for H
and 75 MHz for 13C), for samples in deuterochloroform (unless
otherwise indicated) with tetramethylsilane as internal stand-
1
ard. The multiplicities of the H signals are indicated as: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doub-
let of doublets; dt, doublet of triplets; etc. J-Values are given in
Hz. The multiplicities of 13C NMR signals were determined by
an applied proton test experiment. IR spectra were recorded
on a Perkin-Elmer 1310 spectrometer. The sample was prepared
as a solution in the indicated solvent. Mass spectra were
recorded at the Mass Spectrometry unit, Horticulture Research,
Palmerston North, New Zealand. Microanalyses were carried
out by the staff of the Campbell Microanalytical Laboratory,
University of Otago, Dunedin, New Zealand. Mps were deter-
mined using a Büchi 510 melting-point apparatus and are
uncorrected. Optical rotations were measured using a Perkin-
Elmer 241 polarimeter, in a cell of 1 dm path length. The
concentration (c) is expressed in g/100 mL (equivalent to g/0.1
L) and [α]D-values are given in 10Ϫ1 deg cm2 gϪ1. Analytical
TLC was carried out on pre-coated 0.25 mm thick Merck 60
F254 silica gel plates. Visualisation was by absorption of UV
light, or by thermal development after spraying with basic aq.
potassium permanganate or an ethanolic solution of phos-
phomolybdic acid. Flash chromatography was carried out
using Merck Kieselgel 60 (230–400 mesh) under a pressure of
compressed air. Petroleum spirit refers to the fraction with
distillation range 60–80 ЊC.
(3R,4R,5R,6R)-N-Benzhydryl-3,4,5,6-tetrahydroxyazepane
(؊)-7
Conc. HCl (35 mL) was added dropwise to a stirred solution of
(Ϫ)-6 (5.28 g, 12.9 mmol) in MeOH–CH2Cl2 (2:1; 120 mL). A
suspension formed which was heated to reflux, and after 90 min
it was noted a solution had formed. After being heated for 48 h
the reaction mixture was cooled in an ice-bath and solid
NaHCO3 (45 g) was added carefully over a period of 30 min.
The mixture was filtered, and concentrated in vacuo. The resi-
due was taken up in diethyl ether (200 mL) and the extract
washed with saturated aq. NaHCO3 (150 mL). The aqueous
phase was back-extracted with further diethyl ether (2 × 200
mL). The combined ethereal extract was dried (MgSO4), fil-
tered, and concentrated in vacuo. Silica gel chromatography and
elution with ethyl acetate, followed by 2.5 and 5% MeOH in
ethyl acetate, afforded tetraol (Ϫ)-7 (3.79 g, 89%) as a white
solid (Found: C, 69.3; H, 7.1; N, 4.2. C19H23NO4 requires C,
69.28; H, 7.04; N, 4.25%); mp 135 ЊC; [α]D22 Ϫ87 (c 0.86, CHCl3);
νmax (CDCl3)/cmϪ1 3539, 3086, 3064, 3029, 2890, 2838, 1952,
1893, 1811, 1600, 1453, 1252, 1054; δH (CD3OD) 7.42–7.38 (4H,
m), 7.35–7.05 (6H, m), 4.67 (1H, s), 4.07–4.01 (4H, m), 2.80
(2H, dd, J 13.2, 5.0), 2.66 (2H, dd, J 13.2, 7.5); δC (CD3OD)
144.8 (C), 144.7 (C), 130.1 (CH), 130.0 (CH), 129.6 (CH),
2,3:4,5-Di-O-isopropylidene-D-manno-hexodialdose (؊)-517
Aq. sodium periodate (5.20 g, 24.3 mmol in 20 mL) was heated,
with stirring, to 75 ЊC over a period of 20 min. Silica (20 g) was
added to the stirred solution. The mixture was then cooled and
shaken vigorously for 20 min to give a coarse powder. CH2Cl2
1158
J. Chem. Soc., Perkin Trans. 1, 2000, 1157–1159