Stereocontrolled synthesis of enantiomeric imidazolopiperidinoses and imidazoloazepanoses using Wittig/dihydroxylation reactions

Article abstract of DOI:10.1016/j.tet.2007.01.016

A new route for the synthesis of imidazolosugars-6-deoxyimidazolopiperidinoses 1 and 2 and 7-deoxyimidazoloazepanoses 3?and 4 in two enantiomerical forms-is reported. The new synthetic approach is based on two key reactions: (i) stereocontrolled Wittig Z-

Full text of DOI:10.1016/j.tet.2007.01.016

Tetrahedron 63 (2007) 2915–2922
Stereocontrolled synthesis of enantiomeric imidazolopiperidinoses
and imidazoloazepanoses using Wittig/dihydroxylation reactions
Dariusz Deredas,a Micha1 Skowron,a Emmanuel Salomon,c Celine Tarnus,c
c
Theophile Tschamber, Wojciech M. Wolf and Andrzej Frankowski
b
a,
*
ꢀ
a
_
Institute of Organic Chemistry, Technical University of Lodz, ul. Zeromskiego 116, 90-924 Lodz, Poland
b
_
Institute of General and Ecological Chemistry, Technical University of Lodz, ul. Zeromskiego 116, 90-924 Lodz, Poland
c
´
Ecole Nationale Superieure de Chimie, Universite de Haute-Alsace, 3 rue Alfred Werner, 68093 Mulhouse, France
´
Received 21 July 2006; revised 21 December 2006; accepted 11 January 2007
Available online 13 January 2007
Abstract—A new route for the synthesis of imidazolosugars—6-deoxyimidazolopiperidinoses 1 and 2 and 7-deoxyimidazoloazepanoses
3 and 4 in two enantiomerical forms—is reported. The new synthetic approach is based on two key reactions: (i) stereocontrolled Wittig
Z-olefination of an imidazolecarbaldehyde with phosphoranes containing one chiral centre, obtained from (S)- and (R)-1,2,4-butantriol;
(ii) diastereoselective cis-dihydroxylation of previously obtained olefins. All synthesised imidazolosugars were evaluated as potential inhib-
itors of glycosidases.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Imidazolosugars, as potential glycosidase inhibitors, have
been the subject of interest of several research groups.15–18
Our previous research in this area concerned the syntheses
of imidazolopyrrolidinoses19 and imidazolopiperidinoses.20
In addition, one imidazoloazepanose has been reported
by us so far.21 All our products have been obtained in
multistep synthetic pathways from the respective monosac-
charides.
Among the natural and synthetic inhibitors of glycosidases
there are structural analogues of monosaccharides in which
the endocyclic oxygen atom is replaced by a nitrogen atom.
Thus, naturally occurring polyhydroxylated pyrrolidines
(pyrrolidinoses), such as DMDP (2,5-bis-hydroxymethyl-
3,4-dihydroxy-pyrrolidine),1 and polyhydroxylated piperi-
dines (piperidinoses), such as DNJ (1-deoxynojirimycin),2
exhibit specific glycosidase inhibitoryactivity. In recent years
some efforts have been directed to the synthesis of the seven-
membered ring analogues, the polyhydroxyazepanes (azepa-
noses).3–9 Some of them exhibit even higher inhibition
potency than their five- and six-membered counterparts.10
We now report the syntheses of novel imidazolopiperidino-
ses 1 and 2 and imidazoloazepanoses 3 and 4, each in both
enantiomeric forms.
OH
N
OH
7
HO
HO
8
6
The enzymatic mechanism of catalytic polysaccharide hy-
drolysis, using glycosidases, has been well studied. The pu-
tative oxocarbenium ion-like transition state (TS), which is
presumably produced during both glycosylation and degly-
cosylation steps of glycosides, appears to be in a half-chair
conformation. This TS can be mimicked by some putative
inhibitors, for example, with azasugars fused to a tetrazole,
a triazole or an imidazole.11,12 In 1991 we reported the first
synthesis of the imidazolosugars.13 In 1992 it was showed
that the natural imidazolosugar nagstatine is a very potent
inhibitor of N-acetyl-glucosaminidases.14
X
Y
X
Y
8a
5
N
3
1
N
N
1 X = H, Y = CH2OH
ent-2 X = CH2OH, Y = H
ent-1 X = CH2OH, Y = H
2 X = H, Y = CH2OH
OH
OH
HO
HO
8
7
X
Y
X
Y
9
6
9a
1
N
N
N
3
5
N
3 X = H, Y = OH
ent-4 X = OH, Y = H
ent-3 X = OH, Y = H
4 X = H, Y = OH
* Corresponding author. E-mail: andfrank@p.lodz.pl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.016

2916
D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
2. Results and discussion
Triphenylphosphonium iodide 8, obtained from 7 in 92%
yield, and 4-formyl-1-tritylimidazole25 were used as com-
ponents in the Wittig olefination. High Z-stereoselectivity
(Z/E¼93:7) was achieved owing to a suitable selection of
bases (NaNH2/tBuOK¼9:1).26 The Z-olefin 9 was isolated
in 69% yield from the Z/E mixture by flash chromatography.
2.1. Synthetic strategy
Our approach is based on two key reactions:
(i) stereocontrolled Wittig olefination of chiral phosphor-
anes, obtained from (S)- and (R)-1,2,4-butantriol, with
imidazolecarbaldehyde, to yield, after subsequent cyc-
lisation, the mixture of olefins 5 and 6 and ent-5 and
ent-6, respectively.
(ii) Diastereoselective cis-dihydroxylation of olefin 5 to
imidazolopiperidinoses 1 and 2, and olefin 6 to imid-
azoloazepanoses 3 and 4 (Scheme 1). In the same con-
ditions from olefin ent-5 imidazolopiperidinoses ent-1
and ent-2, and from olefin ent-6 imidazoloazepanoses
ent-3 and ent-4 were obtained.
Following the acid removal of the protecting groups (HCl/
THF) leading to 10, subsequent tosylation in pyridine at
ꢀ10 ꢁC gave the ditosylate 11. Crude 11 without isolation,
treated with sodium hydroxide in water and acetone (2:1)
gave the mixture of (S)-imidazoazepinol 6 and (R)-hydroxy-
methyl-imidazopyridine 5 in a 3:1 ratio (Scheme 1). The
formation of this mixture suggests the reaction pathway
via the epoxide 12, followed by the opening of epoxy func-
tion leading to imidazoazepinol 6 (7-endo-tet-cyclisation)
and hydroxymethylpyridine 5 with inversion in configura-
tion at C-5 (6-exo-tet-cyclisation)27 (Scheme 2).
O
O
a
b
+
O
O
O
N
I
Ph
P
OH
N
3 I
-
O
c
N
Tr
8
a
7
9
N
5
6-exo-tet
a
N
OH
OTs
O
N
b
N
N
b
OR
H
Ts
OH
N
N
OH
7-endo-tet
N
11
12
OH
N
H
N
d
N
10
5
R = H
g
h
6
13 R = TBDPS
e
+
Scheme 2. Proposed pathways of cyclisation.
OH
OTs
N
N
OH
Ts
Separation of 5 and 6 appeared very difficult by means of
flash chromatography. However, the imidazoazepinol 6 crys-
tallises partially from the mixture when dissolved in ethyl
acetate/methanol (10:1). The complete separation of 5 and
6 was achieved after selective protection of the primary alco-
hol function of 5.
N
11
N
6
OH
N
OH
N
HO
HO
f
+
OR
13
OR
N
N
Thus the mother liquor was treated with tert-butyldiphenyl-
silyl chloride (TBDPSCl) in pyridine to give the O-silylated
derivative 13, easily isolated by flash chromatography. After
removal of the silyl protecting group from 13 by means of
tetrabutylammonium fluoride (TBAF) in THF, pure 5 was
obtained in 71% yield.
16 R = TBDPS
R = H
15 R = TBDPS
1
h
h
2
R = H
OH
OH
HO
HO
The same reaction conditions as used in the preparation of
olefins 5 and 6 were applied for the synthesis of olefins
ent-5 and ent-6, starting from (R)-1,2-O-isopropylidene-
1,2,4-butantriol, accessible from L-ascorbic acid by the
known procedure.28–30
OH
OH
f
+
6
N
N
N
N
3
4
Scheme 1. Reagents and conditions: (a) Ph3P, toluene, reflux, 30 h; (b)
NaNH2/tBuOK 9:1, ether, rt, 4 h, then 4-formyl-1-tritylimidazole in THF
at ꢀ75 ꢁC; (c) 2 M HClaq/THF, 6 h, 40 ꢁC; (d) TsCl, pyridine, ꢀ10 ꢁC,
12 h; (e) 1 M NaOHaq, acetone, rt, 12 h; (f) K2OsO4$2H2O, K3Fe(CN)6,
2.3. Diastereoselective cis-dihydroxylations
t
K2CO3 and MeSO2NH2, BuOH/H2O (1:1), 48 h, 45 ꢁC; (g) TBDPSCl,
DMAP, pyridine, rt, 12 h; (h) TBAF, THF, rt, 12 h.
The cis-dihydroxylations of olefins 5 and 6 were performed
in catalytic conditions using K2OsO4$2H2O (0.06 equiv) as
a nonvolatile Os source in combination with K3Fe(CN)6
(3 equiv) as co-oxidant in the presence of K2CO3 (3 equiv)
and MeSO2NH2 (2 equiv) in the two-phase BuOH/H2O
(1:1) system.31 We utilised only the internal asymmetric in-
duction caused by the existing chiral centre without resorting
2.2. Z-Wittig olefination and cyclisation
t
(S)-1,2,4-Butantriol, readily accessible from S-malic acid,22
was transformed by the known procedure23,24 to iodide 7.

D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
2917
to external sources of chirality. The cis-dihydroxylations of
dihydroimidazoazepinol 6 or ent-6 proceeded preferentially
from the opposite side to the hydroxy group on the existing
chiral centre, to give the mixture of 3 and 4 or ent-3 and ent-
4 diastereomers, respectively, in a 3:1 ratio. The diastereo-
mers 3 and 4 were separated by flash chromatography.
The cis-dihydroxylation of both enantiomers of dihydro-
hydroxymethyl-imidazopyridine 5 resulted in the formation
of a chromatographically inseparable mixture of diastereo-
mers 1 and 2. Therefore, the olefin 5 was silylated under
standard conditions to give TBDPS derivative 13. The
dihydroxylation of compound 13 led to mixture of diaste-
reomers 15 and 16. Isomers 15 and 16 were chromato-
graphically separated and isolated in a 2:1 ratio (63%
overall yield).
The preference of attack of the oxidative agent from the op-
posite side to the existing TBDPSOCH2 group is a conse-
quence of steric hindrance caused by the bulky silyl group.
The silyl group of 15 was removed by treatment with
Bu4NF to give pure 1 in 60% yield. The same reaction start-
ing from 16 led to the formation of 2 in 60% yield.
The enantiomers ent-1, ent-2, ent-3 and ent-4 were obtained
in the same reaction conditions as used above starting from
olefins ent-5 and ent-6.
2.4. Structural analysis
Structures of (6S)-6,7-dihydro-5H-imidazo[1,5-a]azepine-
6-ol 6, (6S,8S,9R)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]-
azepin-6,8,9-triol
3 and (6R,8R,9S)-6,7,8,9-tetrahydro-
5H-imidazo[1,5-a]azepin-6,8,9-triol ent-3 were clearly
demonstrated by the X-ray diffraction analysis as shown
in Figure 1. The molecules adopt an extended conformation
with the planar imidazole moiety fused with the seven-
membered azepine ring along the aromatic N2–C7 bond.
In 6 the latter is constrained by the endocyclic C5]C6
double bond and exists in the distorted envelope conforma-
tion with C2, N2, C7, C6, C5 and C4 almost coplanar and
C3 situated at the flap. The 3 and ent-3 are enantiomers
with virtually the same conformation. In particular, the aze-
pine ring adopts a chair conformation. The C2, C3, C5 and
C6 atoms form the central plane of the chair while C4 and
both N2 and C7 atoms are situated at the opposite flaps. Al-
though imidazole and azepine fragments exist in a number
of compounds investigated by X-ray analysis the combina-
tion in which they are fused along the aromatic 1,5 bond is
unique among the crystal structures reported to date (Cam-
bridge Structural Database,32 version 5.27, January 2006
update). In all investigated compounds the hydroxyl hydro-
gen atoms bonded to O1 are involved in strong intermolec-
ular hydrogen bonds with the imidazole N1 atoms. In 3 and
ent-3 those interactions are supplemented by intermolecu-
lar hydrogen bonds in which the hydroxyl O2 and O3 atoms
are also involved.
Figure 1. Molecular structures of 6, 3 and ent-3. Displacement ellipsoids
are drawn at the 50% probability level.
Structures of both imidazolopiperidinoses 1 and 2 were
deduced from 1H and 13C NMR spectra by application
of the nuclear Overhauser effect (NOE). For example,
in compound ent-1 cross signal H6–H8 was observed in
two dimensional ROESY spectrum, cross signal H5–H7
was found in compound ent-2 (see numbering given in
Section 1).

2918
D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
2.5. Enzymatic assays
[10-(triphenylmethyl)-10H-imidazol-40-yl]-4,5-O-iso-
propylidene-pent-1-en-4,5-diol (ent-9). To the phos-
phonium iodide 8 (3.12 g, 6 mmol) were added NaNH2
(398 mg, 10.2 mmol), BuOK (45 mg) and anhydrous Et2O
Compounds 1, 2, 3 and 4, in both enantiomeric forms, have
been evaluated as potential inhibitors of six commercially
available glycosidases. Compound 1 as the (5S,7R,8S) enan-
tiomer inhibited the a-D-galactosidase (Aspergillus niger)
with Ki value of 120 mM (IC50¼240 mM +/ꢀ18 mM), while
the (5R,7S,8R) enantiomer was inactive towards this en-
zyme. The remaining compounds were inactive towards
the pool of evaluated D-glycosidases.
t
(15 ml) under argon at room temperature. The mixture was
stirred at room temperature for 4 h. To the stirred dark yellow
suspension was added dropwise a solution of 4-formyl-1-
tritylimidazole (2.04 g, 6 mmol) in anhydrous THF at
ꢀ78 ꢁC. The stirring was continued at ꢀ78 ꢁC overnight.
Then water (60 ml) was added and the reaction mixture was
extracted with CH2Cl2 (3ꢂ100 ml). The organic layer was
dried (MgSO4), filtered and concentrated in vacuo. The resi-
due was purified by flash chromatography (CH2Cl2/acetone
2:1) to give 9 as pale yellow foam (1.89 g, 69%). Rf
(CH2Cl2/acetone 2:1) 0.64; [a]D +17.1 (c 1.00, CHCl3);
nmax (film): 3192, 3024, 3008, 2992, 1552, 1512, 1492, 1464,
1288, 1176, 1100, 764, 720 cmꢀ1; dH (250 MHz, CDCl3) 7.42
(1H, d, J 1.0 Hz, C(20)H), 7.39–7.38 (9H, m, H arom.), 7.19–
7.12 (6H, m, H arom.), 6.77 (1H, d, J 1.0 Hz, C(40)H), 6.33
(1H, d, J 11.6 Hz, C(1)H), 5.56 (1H, dt, J 11.6, 7.0 Hz,
C(2)H), 4.27–4.17 (1H, m, C(4)H), 4.01 (1H, dd, J 8.0,
6.0 Hz, C(5)HaHb), 3.58 (1H, dd, J 8.0, 7.6 Hz, C(5)HaHb),
2.82 (2H, dt, J 7.3, 1.5 Hz, C(3)HaHb, C(3)HaHb), 1.37 (3H,
s, CH3), 1.34 (3H, s, CH3); dC (60 MHz, CDCl3) 142.3 (C
s-arom.), 138.9 (C-50), 138.5 (C-20), 129.7 (C o-arom.),
128.0 (C m-arom. and C p-arom.), 124.7 (C-1), 123.1 (C-40),
120.8 (C-2), 108.7 (C(CH3)2), 75.6 (CPh3), 75.2 (C-4), 68.9
(C-5), 32.8 (C-3), 26.8 (CH3), 25.6 (CH3). HRMS (CI, NH3)
MH+, found: 451.2386; C30H31N2O2 requires: 451.2387.
3. Experimental
3.1. General
Flash chromatography: silica gel (Merck 60, 230–400 mesh).
TLC: silica gel on plastic sheets (Merck 60 HF254); the spots
were viewed under UV or by heating with a heatgun after
spraying with a solution of KMnO4 (20 g) and Na2CO3 (40 g)
€
in H2O (1 l). Mp: Buchi-SMP-30 apparatus; corrected values.
Optical rotations were measured at 20 ꢁC: Perkin–Elmer 241
1
polarimeter. H and 13C NMR spectra: Bruker 250 AC 250
spectrometerat300 K. Internalreferencesfor1HNMR:SiMe4
(d¼0.00), CDCl3 (d¼7.26), CD3OD (d¼3.30), [D4]TSP for
spectra in D2O (d¼0.00); for 13C NMR: CDCl3 (d¼77.03),
CD3OD (d¼49.02); d in parts per million and J in hertz.
HRMS: Finnigan MAT 95 (Finnigan MAT GmbH, Germany).
3.1.1. (S)-3,4-O-Isopropylidene-3,4-dihydroxybutyltri-
phenylphosphonium iodide (8) and (R)-3,4-O-isopropyl-
idene-3,4-dihydroxybutyltriphenylphosphonium iodide
(ent-8). To a stirred solution of iodide 724 (8.31 g, 33 mmol)
in anhydrous toluene (30 ml) was added dropwise a solution
of triphenylphosphine (12.80 g, 49 mmol) in anhydrous tolu-
ene(60 ml)atroomtemperature. Themixturewasrefluxedfor
30 h until complete disappearance of 7 (TLC). The resulting
suspension was filtered and the solid was washed with toluene
and Et2O to obtain 8 (15.55 g, 92%) as colourless crystals. Mp
219–221 ꢁC; [a]D +2.62 (c 1.00, CHCl3); nmax (KBr): 3112,
2864, 1584, 1560, 1480, 1432, 1372, 1252, 1108, 696, 664,
620 cmꢀ1; dH (250 MHz, CDCl3) 7.85–7.72 (15H, m, H
arom.), 4.56–4.51 (1H, m, C(3)H), 4.47–4.28 (1H, m,
C(1)HaHb), 4.16 (1H, dd, J 8.6, 6.4 Hz, C(4)HaHb), 3.62
(1H, dd, J 8.6, 5.6 Hz, C(4)HaHb), 3.58–3.39 (1H, m,
C(1)HaHb), 2.21–2.06 (1H, m, C(2)HaHb), 1.82–1.60 (1H,
m, C(2)HaHb), 1.32 (3H, s, CH3), 1.29 (3H, s, CH3); dC
The same procedure as for the preparation of 9 was used
starting from ent-8 to give ent-9 as pale yellow foam with
the same yield.
ent-9: [a]D ꢀ16.9 (c 1.00, CHCl3).
3.1.3. (S)(Z)-1-(Imidazol-40(50)-yl)pent-1-en-4,5-diol (10)
and (R)(Z)-1-(imidazol-40(50)-yl)pent-1-en-4,5-diol (ent-
10). To a stirred solution of 9 (92.67 g, 5.93 mmol) in THF
(20 ml) was added 2 M HCl (36 ml). The stirring was contin-
ued at 40 ꢁC for 6 h. The reaction mixture was neutralised
with saturated aq K2CO3 solution, concentrated in vacuo
and coevaporated several times with dry ethanol in order
to remove water. The residue was extracted a few times
with dry ethanol and after evaporation was purified by flash
chromatography (CHCl3/EtOH 2:1) to give 10 (895 mg,
90%) as a colourless foam. Rf (CHCl3/EtOH 2:1) 0.30;
[a]D +20.1 (c 1.00, MeOH); nmax (film): 3500, 3440, 3232,
4
(60 MHz, CDCl3) 134.78 and 134.73 (d, JC–P 3 Hz, C
p-arom.), 133.43 and 133.27 (d, JC–P 10 Hz, C o-arom.),
2
1640, 1592, 1464, 1360, 1264, 1216, 1088, 956, 832 cmꢀ1
;
3
130.42 and 130.22 (d, JC–P 12 Hz, C m-arom.), 118.2 and
116.8 (d, JC–P 678 Hz, C s-arom.), 108.8 (C(CH3)2), 72.7
dH (250 MHz, acetone-d6) 7.68 (1H, s, C(20)H), 7.11 (1H,
s, C(40)H), 6.27 (1H, d, J 11.6 Hz, C(1)H), 5.61 (1H, dt, J
11.6, 8.3 Hz, C(2)H), 3.72 (1H, dddd, J 6.0, 5.7, 5.2,
4.6 Hz, C(4)H), 3.51 (1H, dd, J 10.9, 4.6 Hz, C(5)HaHb),
3.47 (1H, dd, J 10.9, 5.7 Hz, C(5)HaHb), 2.87–2.75 (2H,
m, C(3)HaHb, C(3)HaHb); dC (60 MHz, CD3OH) 136.6
(C-20), 135.3 (C-50), 127.4 (C-2), 122.9 (C-1), 121.8 (C-
40), 73.2 (C-4), 66.6 (C-5), 34.3 (C-3). HRMS (CI, NH3)
MH+, found: 169.0977; C8H13N2O2 requires: 169.0979.
1
(C-3), 68.4 (C-4), 30.6 (C-2), 26.5 (CH3), 24.8 (CH3), 19.8
and 19.0 (d, 1JC–P 48 Hz, C-1). HRMS (CI, NH3) MH+, found:
519.0948; C25H28PO2I requires: 519.0950.
The same procedure as for the preparation of 8 was used
starting from ent-7 (9.23 g, 36.6 mmol) to give ent-8 as
a colourless crystals (17.3 g, 93%).
ent-8: [a]D ꢀ2.7 (c 1.00, CHCl3).
3.1.2. (S)(Z)-1-[10-(Triphenylmethyl)-10H-imidazol-40-yl]-
4,5-O-isopropylidene-pent-1-en-4,5-diol (9) and (R)(Z)-1-
The same procedure as for the preparation of 10 was used
starting from ent-9 to give ent-10 as a colourless foam.
ent-10: [a]D ꢀ20.0 (c 1.00, MeOH).

D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
2919
3.1.4. (5R)-5-tert-Butyldiphenylsilyloxymethyl-5,6-di-
ent-6: [a]D ꢀ63.0 (c 1.00, MeOH).
ent-13: [a]D ꢀ0.9 (c 1.00, CHCl3).
hydroimidazo[1,5-a]pyridine (13), (6S)-6,7-dihydro-5H-
imidazo[1,5-a]azepine-6-ol (6) and (5S)-5-tert-butyldi-
phenylsilyloxymethyl-5,6-dihydroimidazo[1,5-a]pyri-
dine (ent-13), (6R)-6,7-dihydro-5H-imidazo[1,5-a]-
azepine-6-ol (ent-6). To a stirred solution of compound 10
(720 mg, 4.28 mmol) in anhydrous pyridine (32 ml) was
added TsCl (2.28 g, 11.98 mmol) at ꢀ10 ꢁC. The stirring
was continued overnight at ꢀ10 ꢁC until the disappearance
of the starting material (TLC). Water (10 ml) was added to
the reaction mixture at ꢀ5 ꢁC and stirring was continued at
this temperature for 1 h. After extraction with CH2Cl2
(5ꢂ30 ml) the organic layer was concentrated in vacuo and
aq NaOH solution (1 M, 108 ml) and acetone (50 ml) were
added to the residue. The reaction mixture was stirred over-
night at room temperature. After concentration in vacuo
the residue was purified by flash chromatography (CHCl3/
EtOH 3:1) to give the mixture of 6 and 5 in a 3:1 ratio
(NMR). The azepinol 6 (219 mg) partially crystallised from
the mixture 6 and 5 dissolved in AcOEt/MeOH (10:1). The
mother liquor was evaporated in vacuo to dryness.
3.1.5. (5R)-5,6-Dihydro-5-hydroxymethyl-imidazo[1,5-a]-
pyridine (5) and (5S)-5,6-dihydro-5-hydroxymethyl-
imidazo[1,5-a]pyridine (ent-5). To a stirred solution of 13
(422 mg, 1.17 mmol) in anhydrous THF (3 ml) the solution
of TBAF in THF (1.1 M, 2.2 ml, 2.34 mmol) was added.
The mixture was stirred at room temperature overnight until
the disappearance of the starting material (TLC). After evap-
oration in vacuo the residue was purified by flash chromato-
graphy to give 5 (16 mg, 71%) as a colourless film. Rf
(CHCl3/EtOH/25% aq NH3 20:10:1) 0.60; [a]D ꢀ54.0 (c
1.00, MeOH); nmax (film): 3416, 3032, 2968, 2904, 2872,
1656, 1520, 1464, 1400, 1288, 1248, 1056, 884, 664,
620 cmꢀ1; dH (250 MHz, CH3OD) 7.68 (1H, s, C(3)H),
6.83 (1H, s, C(1)H), 6.47 (1H, d, J 10.0 Hz, C(8)H), 5.77
(1H, dt, J 10.0, 5.0 Hz, C(7)H), 4.29 (1H, m, C(5)H), 3.65
(2H, m, C(9)HaHb, C(9)HaHb), 2.54 (2H, m, C(6)HaHb,
C(6)HaHb); dC (60 MHz, CH3OD) 137.8 (C-3), 128.6 (C-
8a), 124.8 (C-1), 122.3 (C-7), 117.8 (C-8), 64.0 (C-9), 55.7
(C-5), 26.5 (C-6); FABMS: 151.0 ([M+H]+). HRMS (CI,
NH3) MH+, found: 151.0873; C8H11N2O requires: 151.0873.
To a stirred solution of the resulted mixture of isomers 5
and 6 (231 mg) in anhydrous pyridine (20 ml) was added
4-dimethylaminopyridine (DMAP) (60 mg), and then tert-
butyldiphenylsilyl chloride (tBuPh2SiCl) (275 mg, 1 mmol)
was added dropwise. The stirring was continued at room
temperature overnight. After evaporation in vacuo the resi-
due was purified by flash chromatography (CHCl3/EtOH
20:1) to give 13 (270 mg) as a yellow thick oil and 6
(99 mg) (CHCl3/EtOH 2:1) as yellowish crystals, which
were recrystallised (AcOEt/MeOH) mp 154–156 ꢁC (dec).
The same procedure as for the preparation of 5 was used
starting from ent-13 to give ent-5 as a colourless film.
ent-5: [a]D +53.9 (c 1.00, MeOH).
3.1.6. (6S,8S,9R)-6,7,8,9-Tetrahydro-5H-imidazo[1,5-a]-
azepin-6,8,9-triol (3), (6S,8R,9S)-6,7,8,9-tetrahydro-5H-
imidazo[1,5-a]azepin-6,8,9-triol (4) and (6R,8R,9S)-
6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-6,8,9-triol
(ent-3), (6R,8S,9R)-6,7,8,9-tetrahydro-5H-imidazo-
[1,5-a]azepin-6,8,9-triol (ent-4). To a stirred solution of
MeSO2NH2 (307 mg, 3.23 mmol), K3Fe(CN)6 (1.27 g,
Compound 13: Rf (CHCl3/EtOH 20:1) 0.30; [a]D +0.9 (c
1.00, CHCl3); nmax (film): 3072, 2992, 2936, 2904, 2856,
1588, 1544, 1472, 1424, 1392, 1200, 1104, 976, 876, 840,
824, 676, 620 cmꢀ1; dH (250 MHz, CDCl3) 7.87–7.29
(11H, m, C(3)H, H arom.), 7.18 (1H, d, J 1.0 Hz, C(1)H),
6.40 (1H, d, J 11.6 Hz, C(8)H), 5.59 (1H, dt, J 11.6,
8.0 Hz, C(7)H), 4.30 (1H, m, C(5)H), 3.76–3.60 (2H,
m, C(9)HaHb, C(9)HaHb), 2.65–2.32 (2H, m, C(6)HaHb,
C(6)HaHb), 1.07 (9H, s, SiC(CH3)3); dC (60 MHz, CDCl3)
136.7 (C-3), 135.4 (C o-arom.), 132.8 and 132.5 (C
s-arom.), 129.8 (C p-arom.), 127.7 (C m-arom.), 126.8 (C-
8a), 125.2 (C-1), 119.5 (C-7), 116.7 (C-8), 65.0 (C-9), 54.04
(C-5), 26.7 (SiC(CH3)3), 25.5 (C-6), 19.0 (SiC(CH3)3).
HRMS (CI, NH3) MH+, found: 389.2049; C24H29N2OSi
requires: 389.2050.
t
3.87 mmol) and K2CO3 (535 mg, 3.87 mmol) in BuOH
(3 ml) and H2O (3 ml) was added K2OsO4$2H2O (24 mg,
0.065 mmol) at room temperature. Then a solution of 6
(194 mg, 1.29 mmol) in tBuOH (4 ml) and H2O (4 ml) was
added dropwise at room temperature. The stirring was con-
tinued at 45 ꢁC for 2 days until the disappearance of the start-
ing material (TLC). The reaction was quenched at 0 ꢁC by
the addition of Na2SO3 (2.03 g, 16.13 mmol), then warmed
to room temperature and stirred for 2 h. After evaporation in
vacuo the solid residue was extracted with EtOH. The
solvent was removed in vacuo and the crude product was
chromatographed (CHCl3/EtOH/25% aq NH3 10:10:1) to
give 3 (132 mg) and 4 (49 mg)) in 76% overall yield.
Compound 6: Rf (CHCl3/EtOH 3:1) 0.20; [a]D +62.9 (c 0.50,
MeOH); nmax (film): 3480, 2144, 3064, 3008, 2992, 2872,
1536, 1504, 1496, 1432, 1256, 1224, 992, 944, 692,
620 cmꢀ1; dH (250 MHz, D2O) 7.58 (1H, s, C(3)H), 6.95
(1H, s, C(1)H), 6.40 (1H, d, J 12.6 Hz, C(9)H), 5.61 (1H,
dt, J 12.6, 7.8 Hz, C(8)H), 4.32–4.07 (3H, m, C(6)H,
C(5)HaHb, C(5)HaHb), 2.77–2.48 (2H, m, C(7)HaHb,
C(7)HaHb); dC (60 MHz, CH3OD) 139.7 (C-3), 132.2
(C-9a), 129.8 (C-1), 123.8 (C-8), 117.2 (C-9), 67.6 (C-6),
54.1 (C-5), 40.3 (C-7). HRMS (CI, NH3) MH+, found:
151.0871; C8H11N2O requires: 151.0873.
Compound 3: Rf (CHCl3/EtOH/25% aq NH3 10:10:1) 0.27;
mp 212–216 ꢁC (dec) (recrystallised from AcOEt/MeOH);
[a]D ꢀ39.6 (c 0.50, MeOH); nmax (film): 3912, 3720,
3344, 3136, 1640, 1532, 1452, 1432, 1384, 1308, 1008,
956, 660, 620 cmꢀ1; dH (250 MHz, CD3OD) 7.53 (1H, s,
C(3)H), 6.89 (1H, s, C(1)H), approx. 4.90 (1H, s, C(9)H—
overlapped with H2O signal from methanol), 4.18 (1H,
dm, J 12.8 Hz, C(5)HaHb), 4.18 (1H, dd, J 12.8, 9.8 Hz,
C(5)HaHb), 3.71 (1H, dddd, J 10.7, 3.7, 1.8, 1.6 Hz,
C(6)H), 3.67 (1H, m, C(8)H), 2.39 (1H, dt, J 12.9,
10.7 Hz, C(7)HaHb), 2.08 (1H, dm, J 12.9 Hz, C(7)HaHb);
dC (60 MHz, CD3OD) 139.9 (C-3), 132.6 (C-9a), 128.8
The same procedure as for the preparation of 13 and 6 was
used starting from ent-10 to give ent-13 and ent-6.

2920
D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
(C-1), 72.1 (C-6), 69.5 (C-8), 69.2 (C-9), 53.5 (C-5), 40.8
(C-7). HRMS (CI, NH3) MH+, found: 185.0927;
C8H13N2O3 requires: 185.0928.
Compound 16: Rf (CHCl3/EtOH 3:1) 0.36; [a]D +18.9 (c
1.00, CHCl3); nmax (film): 3360, 3104, 3072, 2984, 2928,
2872, 2856, 1728, 1520, 1468, 1456, 1424, 1112, 704,
664, 620 cmꢀ1; dH (250 MHz, CD3OD) 7.87 (1H, s,
C(3)H), 7.70–7.39 (10H, m, H arom.), 6.98 (1H, s, C(1)H),
4.79 (1H, d, J 3.4 Hz, C(8)H), 4.32 (1H, dddd, J 6.4, 6.3,
3.9, 0.9 Hz, C(5)H), 4.02–3.88 (3H, m, C(7)H, C(9)HaHb,
C(9)HaHb), 2.16 (1H, ddd, J 12.7, 6.3, 5.2 Hz, C(6)HaHb),
1.93 (1H, ddd, J 12.7, 5.9, 0.9 Hz, C(6)HaHb), 1.06 (9H, s,
(SiC(CH3)3); dC (60 MHz, CD3OD) 136.9 (C-3), 136.7 (C
m-arom.), 133.9 and 133.8 (C s-arom.), 131.2 (C-8a),
129.3 (C o-arom.), 129.0 (C p-arom.), 126.4 (C-1), 68.6
(C-9), 68.4 (C-7), 64.0 (C-8), 56.4 (C-5), 28.5 (C-6), 27.3
(SiC(CH3)3), 19.9 (SiC(CH3)3); FABMS: 423.2 ([M+H]+).
HRMS (CI, NH3) MH+, found: 423.2104; C23H31N2O3Si
requires: 423.2106.
Compound 4: Rf (CHCl3/EtOH/25% aq NH3 10:10:1) 0.34;
mp 196–198 ꢁC (dec) (recrystallised from AcOEt/MeOH);
[a]D +54.6 (c 0.50, MeOH); nmax (film): 3912, 3720, 3344,
3136, 1640, 1532, 1452, 1432, 1384, 1308, 1008, 956,
660, 620 cmꢀ1; dH (250 MHz, CD3OD) 7.59 (1H, s,
C(3)H), 6.95 (1H, s, C(1)H), approx. 4.90 (1H, s, C(9)H—
overlapped with H2O signal from methanol), 4.22–4.13
(3H, m C(8)H, C(5)HaHb, C(5)HaHb), 3.97 (1H, dddd, J
10.9, 4.8, 2.1, 1.5 Hz, C(6)H), 2.25 (1H, ddd, J 13.7, 10.9,
2.1 Hz, C(7)HaHb), 2.02 (1H, dm, J 13.7 Hz, C(7)HaHb);
dC (60 MHz, CD3OD) 140.5 (C-3), 129.9 (C-9a), 128.1
(C-1), 69.9 (C-9) and (C-6), 66.7 (C-8), 52.7 (C-5), 39.2
(C-7). HRMS (CI, NH3) MH+, found: 185.0927;
C8H13N2O3 requires: 185.0928.
The same procedure as for the preparation of 15 and 16 was
used starting from ent-13 to give ent-15 and ent-16.
The same procedure as for the preparation of 3 and 4 was
used starting from ent-6 to give ent-3 and ent-4.
ent-15: [a]D ꢀ6.8 (c 1.40, CHCl3).
ent-16: [a]D ꢀ19.1 (c 1.70, CHCl3).
ent-3: [a]D +39.7 (c 1.00, MeOH).
ent-4: [a]D ꢀ54.5 (c 0.50, MeOH).
3.1.8. (5R,7S,8R)-5,6,7,8-Tetrahydro-5-hydroxymethyl-
imidazo[1,5-a]pyridine-7,8-diol (1) and (5S,7R,8S)-
5,6,7,8-tetrahydro-5-hydroxymethylimidazo[1,5-a]pyri-
dine-7,8-diol (ent-1). To a stirred solution of compound 15
(66 mg, 0.156 mmol) in anhydrous THF (1 ml) was added
the solution of TBAF in THF (1.1 M, 75 ml, 0.312 mmol).
The mixture was stirred at room temperature overnight until
the disappearance of the starting material (TLC). After evap-
oration in vacuo the residue was chromatographed (CHCl3/
EtOH/25% aq NH3 20:10:1). After evaporation of the
solvents the residue was dissolved in H2O (2 ml). This aq
solution was successively passed over Amberlite CG 400
(OHꢀ) and Amberlite CG 120 (H+) columns. Elution of 1
was performed with 2 M aq NH3 to give 1 (17 mg, 59%)
as a yellow film after lyophilisation. Rf (CHCl3/EtOH/25%
aq NH3 20:10:1) 0.14; [a]D +22.9 (c 1.00, H2O); nmax
(film): 3368, 3128, 2936, 2872, 2856, 1552, 1520, 1472,
1404, 1152, 1112, 704, 680, 664, 620 cmꢀ1; dH (250 MHz,
CD3OD) 7.94 (1H, s, C(3)H), 7.08 (1H, s, C(1)H), 4.84
(1H, d, J 3.0 Hz, C(8)H), 4.22 (1H, m, C(5)H), 3.99 (1H,
dt, J 11.6, 3.7 Hz, C(7)H), 3.95 (1H, dd, J 12.2, 3.7 Hz,
C(9)HaHb), 3.75 (1H, dd, J 12.2, 5.5 Hz, C(9)HaHb), 2.09
(1H, dt, J 13.1, 11.6 Hz, C(6)HaHb), 1.93 (1H, dt, J 13.1,
4.3 Hz, C(6)HaHb); dC (60 MHz, CD3OD) 135.4 (C-8a),
129.9 (C-3), 125.2 (C-1), 66.4 (C-7), 62.9 (C-8), 61.6 (C-
9), 54.1 (C-5), 26.1 (C-6). HRMS (CI, NH3) MH+, found:
185.0917; C8H13N2O3 requires: 185.0928.
3.1.7. (5R,7S,8R)-5-tert-Butyldiphenylsilyloxy-methyl-
5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine-7,8-diol (15),
(5R,7R,8S)-5-tert-butyldiphenylsilyloxy-methyl-5,6,7,8-
tetrahydro-imidazo[1,5-a]pyridine-7,8-diol (16) and
(5S,7R,8S)-5-tert-butyldiphenylsilyloxy-methyl-5,6,7,8-
tetrahydro-imidazo[1,5-a]pyridine-7,8-diol (ent-15),
(5S,7S,8R)-5-tert-butyldiphenylsilyloxy-methyl-5,6,7,8-
tetrahydro-imidazo[1,5-a]pyridine-7,8-diol (ent-16). To
a stirred solution of MeSO2NH2 (96 mg, 1.01 mmol),
K3Fe(CN)6 (398 mg, 1.21 mmol) and K2CO3 (167 mg,
1.21 mmol) in tBuOH (2.5 ml) and H2O (2.5 ml) was added
K2OsO4$2H2O (7.4 mg, 0.02 mmol) at room temperature.
t
Then a solution of 13 (145 mg, 0.40 mmol) in BuOH
(3.5 ml) was added dropwise at room temperature. The stir-
ring was continued at 45 ꢁC for two days until the disappear-
ance of the starting material (TLC). Na2SO3 (633 mg,
5.03 mmol) was added at 0 ꢁC and the reaction mixture
was evaporated to dryness. The residue was chromato-
graphed (CHCl3/EtOH 3:1) to give 15 (66 mg) and 16
(33 mg) in 63% overall yield.
Compound 15: Rf (CHCl3/EtOH 3:1) 0.31; [a]D +6.6 (c 1.00,
CHCl3); nmax (film): 3360, 3104, 3072, 2984, 2928, 2872,
2856, 1728, 1520, 1468, 1456, 1424, 1112, 704, 664,
620 cmꢀ1; dH (250 MHz, CD3OD) 7.54 (1H, s, C(3)H),
7.52–7.30 (10H, m, H arom.), 7.01 (1H, s, C(1)H), 4.73
(1H, d, J 3.5 Hz, C(8)H), 4.45 (1H, m, C(5)H), 4.18 (1H,
dt, J 8.2, 2.6 Hz, C(7)H), 3.94 (1H, dd, J 10.9, 5.5 Hz,
C(9)HaHb), 3.81 (1H, dd, J 10.9, 3.8 Hz, C(9)HaHb), 2.30
(1H, ddd, J 14.0, 8.2, 6.1 Hz, C(6)HaHb), 1.96 (1H, ddd,
J 14.0, 6.9, 2.6 Hz, C(6)HaHb), 1.01 (9H, s, (SiC(CH3)3));
dC (60 MHz, CD3OD) 136.7 (C-3), 136.6 (C m-arom.),
134.0 and 133.7 (C s-arom.), 131.2 (C-8a), 129.3 (C
p-arom.), 129.0 (C o-arom.), 126.5 (C-1), 68.2 (C-9), 67.3
(C-7), 65.7 (C-8), 53.7 (C-5), 30.2 (C-6), 27.3 (SiC(CH3)3),
18.4 (SiC(CH3)3). HRMS (CI, NH3) MH+, found: 423.2105;
C23H31N2O3Si requires: 423.2106.
The same procedure as for the preparation of 1 was used
starting from ent-15 to give ent-1.
ent-1: [a]D ꢀ22.7 (c 0.95, H2O).
3.1.9. (5R,7R,8S)-5,6,7,8-Tetrahydro-5-hydroxymethyl-
imidazo[1,5-a]pyridine-7,8-diol (2) and (5S,7S,8R)-
5,6,7,8-tetrahydro-5-hydroxymethylimidazo[1,5-a]pyri-
dine-7,8-diol (ent-2). The same procedure as described for 1
was used starting from 16 (75 mg, 0.177 mmol) to give after
workup compound 2 (19 mg, 59%). Rf (CHCl3/EtOH/25%

D. Deredas et al. / Tetrahedron 63 (2007) 2915–2922
2921
ꢀ3
˚
aq NH3 20:10:1) 0.14; [a]D +14.9 (c 0.50, H2O); nmax (film):
3368, 3128, 2936, 2872, 2856, 1552, 1520, 1472, 1404,
1152, 1112, 704, 680, 664, 620 cmꢀ1; dH (250 MHz,
CD3OD) 7.90 (1H, s, C(3)H), 7.04 (1H, s, C(1)H), 4.73
(1H, d, J 1.8 Hz, C(8)H partially overlapped with H2O signal
from methanol), 4.28 (1H, m, C(5)H), 4.17 (1H, m, C(7)H),
3.89 (1H, dd, J 12.2, 4.3 Hz, C(9)HaHb), 3.63 (1H, dd, J
12.2, 4.9 Hz, C(9)HaHb), 2.20 (1H, ddd, J 9.8, 6.1, 1.8 Hz,
C(6)HaHb), 1.89 (1H, ddd, J 9.8, 7.9, 1.8 Hz, C(6)HaHb);
dC (60 MHz, CD3OD) 135.3 (C-8a), 129.8 (C-3), 124.3
(C-1), 65.1 (C-7), 63.8 (C-8), 63.1 (C-9), 51.4 (C-5), 27.7
(C-6). FABMS: 184.9 ([M+H]+). HRMS (CI, NH3) MH+,
found: 185.0928; C8H13N2O3 requires: 185.0928.
residual electron density Drmax¼0.15, Drmin¼ꢀ0.19 eA
,
Flack parameter with 640 Friedel pairs h¼0.00(19). Crystal-
lographic data deposited as supplementary publication
CCDC 602462.
3.2.3. (6R,8R,9S)-6,7,8,9-Tetrahydro-5H-imidazo[1,5-a]-
azepin-6,8,9-triol (ent-3). Formula C8H12N2O3, Mw¼
184.20, colourless crystal 0.40ꢂ0.15ꢂ0.10 mm, a¼
3
˚
˚
4.8168(1), b¼13.1830(1), c¼13.2008(1) A, V¼838.25(1) A ,
r¼1.460 g cmꢀ3, m¼9.30 cmꢀ1, Z¼4, crystal system: ortho-
rhombic, space group P212121, T¼135 K, u scans (Du¼
0.3ꢁ), 9518 reflections collected (5ꢃhꢃꢀ4; 16ꢃkꢃꢀ16;
16ꢃlꢃꢀ16), 2qmaxꢃ142ꢁ, 1591 unique reflections (Rint¼
0.014) and 1591 observed reflections [Iꢃ2s(I)], 168 refined
parameters, Rall¼0.024, wR(F2)¼0.060, S¼1.06, max (min)
ent-2: [a]D ꢀ15.0 (c 1.00, H2O).
ꢀ3
˚
residual electron density Drmax¼0.16, Drmin¼ꢀ0.20 eA
,
3.2. X-ray diffraction analysis
Flack parameter with 630 Friedel pairs h¼0.01(16). Crystallo-
graphic data deposited as supplementary publication CCDC
602461.
Single crystals were obtained by recrystallisation from ethyl
acetate/n-hexane (1:1) mixture at room temperature. X-ray
diffraction data were collected on a Bruker Smart Apex
CCD area detector diffractometer, graphite-monochromated
3.3. Enzymatic assays
˚
radiation l (Cu Ka¼1.54178 A). All structures were solved
Glycosidases [a-mannosidase (EC 3.2.1.24) from Jack
beans (Sigma M 7257), b-mannosidase (EC 3.2.1.25) from
snail acetone powder (Sigma M 9400), a-glucosidase (EC
3.2.1.20) from baker’s yeast (Sigma G-5003), b-glucosidase
(EC 3.2.1.21) from almonds (Sigma G-4511), a-galactosi-
dase (EC 3.2.1.22) from green coffee beans (Sigma G-
8507), b-galactosidase (EC 3.2.1.23) from Escherichia coli
(Sigma G-4155)] and their corresponding substrates were
purchased from Sigma Co. Spectrophotometric assays
were performed at the optimum pH for each enzyme, with
p-nitrophenyl-a-D-mannopyranoside as a substrate for
a-mannosidase (Km¼5 mM, pH¼4.5), p-nitrophenyl-b-D-
mannopyranoside for b-mannosidase (Km¼0.9 mM, pH¼
4.5), p-nitrophenyl-a-D-glucopyranoside for a-glucosidase
(Km¼0.2 mM, pH¼7), p-nitrophenyl-b-D-glucopyranoside
for b-glucosidase (Km¼5 mM, pH¼5.0), p-nitrophenyl-a-
D-galactopyranoside for a-D-galactosidase (Km¼0.8 mM,
pH¼6.5) and p-nitrophenyl-b-D-galactopyranoside for b-
D-galactosidase (Km¼0.2 mM, pH¼7). The release of p-
nitrophenol was measured continuously at 405 nm with a
spectrophotometer HP-8453 to determine initial velocities.
All kinetics were performed at 25 ꢁC and the reaction was
started by the addition of enzyme in a 1 ml assay medium
(acetate buffer 50 mM or phosphate buffer 20 mM according
to the desired pH value) using substrate concentrations
around the Km value of each enzyme. The substrates were
dissolved in water/ethanol 50:50 (v/v). The Ki value was
determined for the most potent inhibitor, by the Dixon
graphical procedure.38,39
with direct methods and refined on F2 by full matrix least-
squares method. Hydrogen atoms were localised on differ-
ence Fourier maps and further refined with individual
temperature factors. Computer programs used are: data
collection SMART APEX,33 data reduction SAINT-Plus,34
semiempirical absorption correction based on multiple
scanned equivalent reflections SADABS,35 structure solu-
tion, refinement and molecular graphics SHELXTL.36 Crys-
tallographic data (excluding structure factors) for structures
reported herein have been deposited with the Cambridge
Crystallographic Data Centre. Copies of the data can be ob-
tained free of charge on application to: The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk]. Any request
should be accompanied by a full literature citation.
3.2.1. (6S)-6,7-Dihydro-5H-imidazo[1,5-a]azepine-6-ol
(6). Formula C8H10N2O, Mw¼150.18, colourless crystal
0.40ꢂ0.20ꢂ0.10 mm, a¼4.6209(1), b¼7.2461(1), c¼
22.6157(2) A, V¼757.25(1) A , r¼1.317 g cmꢀ3
,
m¼
3
˚
˚
7.27 cmꢀ1, Z¼4, crystal system: orthorhombic, space group
P212121, T¼293 K, u scans (Du¼0.3ꢁ), 8742 reflections
collected (5ꢃhꢃꢀ5; 8ꢃkꢃꢀ8; 27ꢃlꢃꢀ27), 2qmaxꢃ142ꢁ,
1455 unique reflections (Rint¼0.016) and 1452 observed
reflections [Iꢃ2s(I)], 142 refined parameters, Rall¼0.028,
wR(F2)¼0.079, S¼1.08, max (min) residual electron density
Drmax¼0.14, Drmin¼ꢀ0.13 eAꢀ3, Flack parameter37 with
˚
556 Friedel pairs h¼0.05(24). Crystallographic data depos-
ited as supplementary publication CCDC 602460.
3.2.2. (6S,8S,9R)-6,7,8,9-Tetrahydro-5H-imidazo[1,5-a]-
azepin-6,8,9-triol (3). Formula C8H12N2O3, Mw¼184.20,
Acknowledgements
colourless crystal 0.40ꢂ0.20ꢂ0.20 mm, a¼4.8638(1),
We thank the Polish State Committee for Scientific Research
(KBN) for financial support (grant 4T09A06524).
3
˚
˚
b¼13.2335(2), c¼13.2205(2) A, V¼850.94(3) A , r¼
1.438 g cmꢀ3, m¼9.30 cmꢀ1, Z¼4, crystal system: ortho-
rhombic, space group P212121, T¼293 K, u scans (Du¼
0.3ꢁ), 9662 reflections collected (5ꢃhꢃꢀ5; 16ꢃkꢃꢀ15;
16ꢃlꢃꢀ16), 2qmaxꢃ142ꢁ, 1610 unique reflections (Rint¼
0.023) and 1606 observed reflections [Iꢃ2s(I)], 168 refined
parameters, Rall¼0.030, wR(F2)¼0.076, S¼1.06, max (min)
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.01.016.

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18. Deredas, D.; Frankowski, A.; Le Nouen, D.; Tschamber, T.;
References and notes
Streith, J. Helv. Chim. Acta 1995, 78, 1837–1842.
19. Tschamber, T.; Siendt, H.; Tarnus, C.; Deredas, D.;
Frankowski, A.; Kohler, S.; Streith, J. Eur. J. Org. Chem.
2002, 702–712 and references cited therein.
20. Tschamber, T.; Siendt, H.; Boiron, A.; Gessier, F.; Deredas, D.;
Frankowski, A.; Picasso, S.; Steiner, H.; Aubertin, A. M.;
Streith, J. Eur. J. Org. Chem. 2001, 1335–1347.
21. Weinberg, K.; Jankowski, S.; Le Nouen, D.; Frankowski, A.
Tetrahedron Lett. 2002, 43, 1089–1092.
22. Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J. J. Am.
Chem. Soc. 1973, 95, 8749–8757.
1. (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.;
Geoffroy, S.; Foglietti, M. J. Bioorg. Med. Chem. 1997, 5,
519–533; (b) Welter, A.; Jadot, J.; Dardenue, G.; Malier, M.;
Casimir, J. Phytochemistry 1997, 15, 747–749.
2. Watson, A. A.;Fleet, G. W. J.; Asano, N.;Molyneux, R. J.;Nash,
R. J. Phytochemistry 2001, 56, 265–295 and references therein.
3. Farr, R. A.; Holland, A. K.; Huber, E. W.; Peet, N. P.;
Weintraub, P. M. Tetrahedron 1994, 50, 1033–1044.
4. Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1994, 35, 3293–3296.
€
23. Borjeson, L.; Welch, C. J. Tetrahedron 1992, 48, 6325–6334.
5. Lohray, B. B.; Jayamma, Y.; Chatterjee, M. J. Org. Chem. 1995,
60, 5958–5960.
6. Moris-Varas, F.; Qian, X.; Wong, C.-H. J. Am. Chem. Soc.
1996, 118, 7647–7652.
7. Painter, G. F.; Falshaw, A. J. J. Chem. Soc., Perkin Trans. 1
2000, 1157–1159.
8. Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.; Wang,
P. G. Tetrahedron Lett. 2002, 43, 6525–6528.
24. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 295–304.
25. Griffith, R. K.; Pietro, D. A. Synthesis 1983, 576.
26. Schlosser, M.; Schaub, B.; Oliveira-Neto, J.; Jeganathan, S.
Chimia 1986, 40, 244–245.
27. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
28. Grindley, C. J.; Cote, P.; Wickramage, C. Carbohydr. Res.
1985, 140, 215–238.
29. Evans, C. A.; Hewgill, R. T.; Monsour, T. S. Tetrahedron:
Asymmetry 1997, 8, 2299–2302.
9. Tilekar, J. N.; Patil, N. T.; Jadhav, H. S.; Dhavale, D. D.
Tetrahedron 2003, 59, 1873–1876.
30. Saibaba, R.; Sarma, M. S. P.; Abushanab, E. Synth. Commun.
1989, 19, 3077–3086.
10. Qian, X.; Moris-Varas, F.; Fitzgerald, M. C.; Wong, C.-H.
Bioorg. Med. Chem. 1996, 4, 2055–2069.
31. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
32. Allen, F. H. Acta Crystallogr., Sect. B 2002, 58, 380–388.
33. Bruker. SMART APEX, Version 5.629; Bruker AXS: Madison,
WI, 2003.
34. Bruker. SAINT-Plus, Version 6.45A; Bruker AXS: Madison,
WI, 2003.
35. Bruker. SADABS—Bruker Nonius area detector scaling and
absorption correction, Version 2.10; Bruker AXS: Madison,
WI, 2003.
11. Gloster, T. M.; Roberts, S.; Ducros, V. M.-A.; Perugino, G.;
Rossi, M.; Hoos, R.; Moracci, M.; Vasella, A.; Davies, G. J.
Biochemistry 2004, 43, 6101–6109.
12. Zechel, D. E.; Withers, S. G. Acc. Chem. Res. 2000, 33, 11–18.
13. Frankowski, A.; Seliga, C.; Bur, D.; Streith, J. Helv. Chim. Acta
1991, 74, 934–940.
14. (a) Aoyagi, T.; Suda, H.; Uotani, K.; Kojima, F.; Aoyama, T.;
Horiuchi, K.; Hamada, M.; Takeuchi, T. J. Antibiot. 1992, 45,
1404–1408; (b) Aoyama, T.; Naganawa, H.; Suda, H.; Uotani,
K.; Aoyagi, T.; Takeuchi, T. J. Antibiot. 1992, 45, 1557–1558.
15. Burgess, K.; Chaplin, D. A.; Elbein, A. D.; Zeng, Y.
Heterocycles 1994, 37, 673–677.
36. Sheldrick, G. M. SHELXTL, Version 6.12; Bruker AXS:
Madison, WI, 2001.
37. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876–881.
38. La, Y.-T. J. Biol. Chem. 1967, 242, 5474–5480.
39. Segel, I. H. Enzyme Kinetics; Wiley: New York, NY, 1975;
pp 109–144.
16. Tatsuta, K.; Miura, S.; Ohta, S.; Gunji, H. Tetrahedron Lett.
1995, 36, 1085–1088.
17. Granier, T.; Panday, N.; Vasella, A. Helv. Chim. Acta 1997, 80,
979–987.