Synthesis of a trihydroxylated azepane from D-arabinose by way of an intramolecular alkene nitrone cycloaddition

Article abstract of DOI:10.1016/j.tetasy.2004.11.041

The synthesis of 1,6-imino-1,5,6-trideoxy-l-xylo-hexitol, a trihydroxylated azepane, from d-arabinose was achieved by way of an intramolecular alkene nitrone cycloaddition. The final product as well as its bicyclic precursor, (3R,4S,5S)-3,4-dihydroxy-8-ox

Full text of DOI:10.1016/j.tetasy.2004.11.041

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 487–491
Synthesis of a trihydroxylated azepane from D-arabinose by way
of an intramolecular alkene nitrone cycloaddition
a,b
c
Stephane Moutel, Michael Shipman,a, ,ꢀ Olivier R. Martin,b, Kyoko Ikeda and
*
*
´
Naoki Asanoc
aSchool of Chemistry, University of Exeter, Exeter EX4 4QD, UK
b
´
´
´
Institut de Chimie Organique et Analytique, UMR 6005 CNRS-Universite d’Orleans, BP 6759, 45067 Orleans, France
cFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 11 November 2004; accepted 19 November 2004
Abstract—The synthesis of 1,6-imino-1,5,6-trideoxy-L-xylo-hexitol, a trihydroxylated azepane, from D-arabinose was achieved by
way of an intramolecular alkene nitrone cycloaddition. The final product as well as its bicyclic precursor, (3R,4S,5S)-3,4-dihy-
droxy-8-oxa-1-azabicyclo[3.2.1]octane, were evaluated as glycosidase inhibitors.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
While most iminosugars are pyrrolidine or piperidine
derivatives, examples based on smaller as well as larger
ring systems have been reported; in particular, polyhydr-
oxylated azepanes7 including seven-membered-ring
homologues of nojirimycin8 have been described by sev-
eral groups, and we have disclosed recently the first
example of an azocane-based iminosugar analogue.9
Herein we report the synthesis of a new trihydroxylated
azepane,10 1,6-imino-1,5,6-trideoxy-L-xylo-hexitol 1,
that is a ring-expanded isomer of isofagomine, 2, by
way of a methodology based on an internal 1,3-dipolar
cycloaddition, as well as an evaluation of this seven-
membered ring iminoalditol as a glycosidase inhibitor.
Saturated nitrogen heterocycles mimicking carbohy-
drate structures are gaining widespread interest because
of their potent and diverse biological activities: initially
discovered for their properties as glycosidase inhibitors,1
such iminosugars have been found to have activities, for
example, on glycosyltransferases,2 glycogen phosphoryl-
ases,3 UDP-galactose mutase4 and nucleoside-process-
ing enzymes.5 Since these enzymes are involved in
numerous fundamental biological processes, these
carbohydrate mimetics constitute leads for the develop-
ment of new therapeutic agents in a wide range of
diseases.6
In previous studies, we have demonstrated the useful-
ness of the intramolecular cycloaddition of the oxime
derived from an unsaturated sugar aldehyde for the syn-
thesis of amino-cyclopentitols.11 In this context, we have
examined the feasibility of a synthesis of isofagomine
2 by way of an internal cycloaddition of an unsaturated
nitrone. Isofagomine 2 is of interest as a powerful b-glu-
cosidase inhibitor, but its synthesis remains lengthy and
requires a chain-branching step.12 As suggested by a
strategic N,O-reconnection in 2 (Scheme 1), the resulting
bicyclic structure A could be accessible by way of an
intramolecular reaction of a methylene nitrone and an
alkene (as in B). While intermolecular cycloadditions
of methylene nitrones with terminal alkenes have been
shown to proceed with the alternate regioselectivity
(C–C bond formation at the terminal alkene carbon
HO
OH
HO
NH
HO
NH
HO
HO
1
2
*
Corresponding authors. Tel.: +33 2 38 49 45 81; fax: +33 2 38 41 72
81(O.R.M.); e-mail addresses: m.shipman@warwick.ac.uk; olivier.
martin@univ-orleans.fr
ꢀ New address. Department of Chemistry, University of Warwick,
Coventry CV4 7AL, UK.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.041

488
S. Moutel et al. / Tetrahedron: Asymmetry 16 (2005) 487–491
PO
PO
OH
HO
HO
O
PO
PO
NH
N+
N
O
H
2
A
B
Scheme 1.
atom),13 an example of intramolecular reaction in a re-
lated system14 lent support to our idea. We therefore
set out to explore this approach.
H
O
N
H
H
H
OBz
H
BzO
H
H
2. Results and discussion
H
3.4%
6.5%
The synthesis (Scheme 2) began with 5-deoxy-5-iodo-D-
arabinofuranoside 3, obtained in three steps and 63%
yield from D-arabinose, as described by Ferrier and
Haines.15 Treatment of this compound with Zn in the
presence of vitamin B12 as initiator16 gave the 4,5-unsat-
urated pentose derivative 4 in 79% yield, and the alde-
hyde was rapidly converted into oxime 5. Reduction of
the oxime function with sodium cyanoborohydride led
to the corresponding N-alkylated hydroxylamine 6,
which was then treated with gaseous formaldehyde un-
der anhydrous conditions to form methylene nitrone 7.
This compound spontaneously cyclized to form a major
bicyclic hydroxylamine, compound 8, isolated in 56%
8
Figure 1. NOE correlations in 8.
The constitution and stereochemistry of the main cyclo-
addition product 8 are consistent with a mechanism
involving a chair-like transition state structure carrying
two equatorial substituents, and controlled by C–C
bond formation to the less substituted end of the alkene
(Fig. 2). This approach therefore does not provide the
carbon skeleton of isofagomine, but the isomeric aze-
pane ring system.
1
yield. The H and 13C NMR data of this compound
indicated unambiguously that it was the alternate regio-
isomer resulting from C–C bond connection at the ter-
minal alkene carbon. The stereochemical assignments
were established on the basis of its NMR parameters
and extensive NOE studies (Fig. 1).
´
Compound 8 was debenzoylated under Zemplen condi-
tions to provide the unusual bicyclic iminosugar ana-
logue 9. The N–O linkage was then cleaved by
I
OMe
O
a
BzO
BzO
c
b
BzO
D-Arabinose
O
OBz
4
3
BzO
d
e
BzO
BzO
BzO
BzO
N+
N-OH
BzO
NH-OH
BzO
O
6
5
7
OH
HO
HO
f
g
O
O
BzO
HO
HO
N
N
N
H
8
9
1
Scheme 2. Reagents and conditions: (a) Ref. 15; (b) Zn, NH4Cl, vitamin B12, MeOH, rt, 79%; (c) NH2OHÆHCl, pyridine, EtOH, 60 ꢁC, 87%;
(d) NaBH3CN, HCl, pH 3–4, MeOH, À5 ꢁC; (e) HCHO, toluene, Na2SO4, 0 ꢁC then reflux, 56% (over the two steps); (f) MeONa, MeOH, rt, 81%;
(g) H2, Pd/C, MeOH, rt, 99%.

S. Moutel et al. / Tetrahedron: Asymmetry 16 (2005) 487–491
489
at 20–25 ꢁC using a Perkin–Elmer polarimeter (model
41) and specific rotation values are given in 10À1 deg
cm2 gÀ1. NMR spectra were recorded on Bruker
AVANCE DPX 250 and DRX 400 spectrometers with
either TMS or residual protic solvent as internal
reference. IR spectra were recorded on Perkin–Elmer
TF PARAGON 1000 PC spectrophotometer. Mass
spectra were recorded under ion spray conditions on a
Perkin–Elmer SCIEX API 300 spectrometer at the Insti-
tut de Chimie Organique et Analytique, University of
O
≠
BzO
BzO
N
Figure 2. Proposed transition state structure.
Table 1. IC50 values for of 9 and 1 in assays of various glycosidasesa
Enzyme
IC50 (lM)
´
Orleans. Accurate masses were recorded under posi-
9
1
tive-ion electrospray on a Finnigan MAT 900 XLT
high-resolution mass spectrometer.
a-Glucosidase (rice)
b-Glucosidase (almond)
(40.4)
(8.2)
(0)
(47.8)
250
350
4.2. 2,3-Di-O-benzoyl-4,5-dideoxy-D-threo-pent-4-enose 4
a-Galactosidase (coffee beans)
b-Galactosidase (bovine liver)
a-Mannosidase (rat epididymis)
b-Mannosidase (rat epididymis)
a-L-Fucosidase (bovine epididymis)
(42.4)
(0)
(0)
420
(49.2)
(13.4)
59
To a stirred solution of vitamin B12 (37 mg, 27 lmol) in
methanol (85 mL) were successively added zinc dust
(3.00 g, 46 mmol) and ammonium chloride (2.50 g,
46 mmol). The mixture was stirred for 10 min and a
solution of compound 315 (2.22 g, 4.6 mmol) in metha-
nol (5 mL) was added. After 90 min, the mixture was fil-
tered on Celite and the solvent removed under reduced
pressure. Column chromatography (light petroleum–
(13.8)
a Values in brackets are % inhibition of enzyme activity at 1000 lM.
hydrogenolysis, to afford 1,6-imino-1,5,6-trideoxy-L-
xylo-hexitol 1.
ethyl acetate; 5:1then 3):1 provided aldehyde
4
The potential of 9 and 1 as glycosidase inhibitors was
examined towards a panel of glycosidases (Table 1).
Compound 9 was found to be only very weakly active
(40% inhibition of two enzymes at 1mM concentration:
a-glucosidase (rice) and bovine b-galactosidase). The
trihydroxylated azepane 1 however exhibited an inter-
esting activity towards bovine a-L-fucosidase (IC50
59 lM) as well as, to a lesser extent, towards other
glycosidases.
(1.18 g, 79%) as a colourless oil; mmax (thin film)/cmÀ1
3472, 1740, 1601, 1452, 1242, 1106, 709; dH (250 MHz,
CDCl3) 9.70 (s, 1H, H-1), 8.20–8.00 (m, 4H, ArH),
7.70–7.30 (m, 6H, ArH), 6.14 (m, 1H, J3,4 6.0, J3,2 3.8,
H-3), 6.04 (ddd, 1H, J3,4 6.0, J4,5Z 17.0, J4,5E 10.3, H-
4), 5.58 (d, 1H, J3,2 3.8, H-2), 5.55 (d, 1H, J4,5Z 17.0,
H-5Z), 5.41(d, 1H,
J4,5E 10.3, H-5E); dC (62.9 MHz,
CDCl3) 195.3 (C-1), 165.8 (C@O), 165.2 (C@O), 133.9
(CH), 133.7 (CH), 131.2 (CH), 130.1 (CH), 130.0
(CH), 129.9 (CH), 129.8 (CH), 129.3 (C), 128.8 (C),
128.7 (CH), 128.6 (CH), 128.5 (CH), 120.2 (C-5), 78.8,
72.4 (C-2, C-3); m/z 325 [M+H]+.
3. Conclusion
In conclusion, it was shown that the intramolecular 1,3-
dipolar cycloaddition of a N-methylene nitrone derived
from a 4,5-unsaturated pentose gave the bicyclic 8-oxa-
1-azabicyclo[3.2.1]octane ring system by formation of
the C–C bond to the less substituted carbon of the
alkene. The resulting bicyclic product serves as a
precursor of a trihydroxylated azepane, a compound
that exhibits interesting activities as a-L-fucosidase
inhibitor.
4.3. 2,3-Di-O-benzoyl-4,5-dideoxy-D-threo-pent-4-enose
oxime 5
A stirred solution of aldehyde 4 (220 mg, 0.68 mmol),
pyridine (165 lL, 2.03 mmol) and hydroxylamine
hydrochloride (141 mg, 2.03 mmol) in ethanol (5 mL)
was heated at 60 ꢁC for 45 min. After cooling, the etha-
nol was removed under reduced pressure and the residue
taken up in diethyl ether and washed with water. The
organic layer was dried over MgSO4, filtered and the
solvent removed in vacuo. Column chromatography
(light petroleum–ethyl acetate; 4:1) provided oxime 5
(200 mg, 87%) as a colourless, oily, 7:3 mixture of E
and Z isomers, mmax (thin film)/cmÀ1 3428, 1731, 1601,
1452, 1257, 1107, 946, 711; dH (250 MHz, CDCl3) 9.60
(br s, 0.3H, OHZ), 9.30 (br s, 0.7H, OHE), 8.18–7.95
(m, 4H, ArH), 7.70–7.30 (m, 7.7H, ArH, H-1E), 6.86
(d, 0.3H, J1,2 5.8, H-1Z), 6.47 (dd, 0.3H, J1,2 5.8, J2,3
4.4, H-2Z), 6.15–5.90 (m, 2.7H, H-2E, H-3, H-4), 5.60–
5.30 (m, 2H, 2 · H-5); dC (62.9 MHz, CDCl3) 165.5
(C@O), 165.4 (C@O), 147.0 (C-1Z), 146.2 (C-1E), 133.6
(CH), 133.5 (CH), 133.4 (CH), 131.5, 131.4 (C-4E, C-
4Z), 130.0 (CH), 129.9 (CH), 129.7 (C), 129.6 (C),
129.4 (C), 129.3 (C), 128.7 (CH), 128.6 (CH), 120.5
(C-5E), 119.9 (C-5Z), 73.9 (C-3E), 73.7 (C-3Z), 71.7 (C-2E),
4. Experimental
4.1. General methods
Reactions requiring anhydrous conditions were per-
formed using oven-dried glassware and conducted under
a positive pressure of argon. Anhydrous solvents were
prepared by standard protocols and were freshly
distilled. All reactions were monitored by TLC on
0.2 mm Merck silica gel plates (60F254) using UV light,
ethanol–sulfuric acid (10:1) solution or 2% phosphomo-
lybdic acid solution as developing agent. Flash column
chromatography was performed on Merck silica gel 60
(0.036–0.063 mm). Optical rotations were determined

490
S. Moutel et al. / Tetrahedron: Asymmetry 16 (2005) 487–491
68.2 (C-2Z); m/z 362 [M+Na]+, 357 [M+NH4]+, 340
[M+H]+; HRMS: found: MH+, 340.1187. (C19H17NO5
requires m/z 340.1185).
H-2eq enhances H-7ax (4.3%), H-2ax (20.2%) and H-3
(7.8%) (Fig. 2).
4.6. (3R,4S,5S)-3,4-Dihydroxy-8-oxa-1-azabicyclo-
[3.2.1]octane 9
4.4. 2,3-Di-O-benzoyl-1,4,5-trideoxy-1-hydroxylamino-D-
threo-pent-4-enitol 6
A solution of sodium methoxide (produced from fresh
sodium shavings) in methanol (1mL) was added to a
solution of bicyclic compound 8 (60 mg, 0.17 mmol) in
methanol (0.5 mL) at 0 ꢁC. The mixture was allowed
to warm up to room temperature, stirred for 2 h, then
neutralized with a mixture of AcOH and MeOH (1:3,
v/v) and concentrated in vacuo. The residue was purified
by flash column chromatography (CH2Cl2–MeOH; 8:1)
to provide bicyclic compound 9 (20 mg, 81%) as a white
solid; [a]D = À52 (c 0.99, MeOH); mmax (KBr)/cmÀ1
3406, 1650, 1092; dH (250 MHz, CD3OD) 4.34 (dd,
1H, J5,4 3.9, J5,6eq 7.3, H-5), 3.64 (ddd, 1H, J3,2eq 6.4,
J3,2ax 10.0, J4,3 8.6, H-3), 3.55 (dd, 1H, J4,5 3.9, J4,3
8.6, H-4), 3.16–3.07 (m, 2H, H-7eq, H-7ax), 3.07 (dd,
1H, J3,2eq 6.4, J2ax,2eq 13.7, H-2eq), 2.88 (dd, 1H, J3,2ax
10.0, J2eq,2ax 13.7, H-2ax), 2.32 (m, 1H, J6ax,6eq 15.4,
J6ax,7eq 7.3, J6ax,7ax 12.7, H-6ax), 2.08 (m, 1H, J6ax,6eq
15.4, J6eq,7ax = J5,6eq 7.3, J6eq,7eq 12.7, H-6eq), dC
(62.9 MHz, CD3OD) 79.6 (C-5), 74.3 (C-4), 67.5 (C-3),
61.9 (C-2), 53.6 (C-7), 29.9 (C-6); m/z 146 [M+H]+;
HRMS found: MH+, 146.0815 (C6H11NO3 requires
m/z 146.0817).
Sodium cyanoborohydride (60 mg, 0.95 mmol) was
added at À5 ꢁC to a stirred solution of oxime 5
(124 mg, 0.36 mmol) and a few drops of methyl orange
indicator in dry methanol (3 mL) under nitrogen. A
solution of hydrochloric acid in methanol (6 M) was
added dropwise to keep the solution pink (pH 3). The
solution was stirred for 30 min and quenched with aque-
ous sodium hydroxide (20%) and then poured into ice
brine. The aqueous suspension was extracted at 0 ꢁC
with dichloromethane (2·) and the organic phase dried
over MgSO4, filtered and the solvent removed in vacuo.
The hydroxylamine 6 was used in the next step without
further purification.
4.5. (3R,4S,5S)-3,4-Dibenzoyloxy-8-oxa-1-azabicyclo-
[3.2.1]octane 8
Gaseous formaldehyde, prepared from paraformalde-
hyde by heating a flask containing the solid with a flame,
was bubbled into a solution of crude hydroxylamine 6 in
dry toluene (8 mL) under nitrogen at 0 ꢁC containing
anhydrous sodium sulfate (500 mg). The mixture was
stirred for 45 min at 0 ꢁC and then heated at reflux for
24 h. On cooling, the mixture was filtered through a
pad of Celite and the solvent was removed in vacuo.
The residue was purified by flash column chromatogra-
phy (light petroleum–ethyl acetate; 1:1) to provide bicy-
clic compound 8 (73 mg, 56% over two steps) as a yellow
solid; [a]D = À147 (c 1.05, CHCl3); mmax (KBr)/cmÀ1
1728, 1601, 1452, 1276, 1108, 709; dH (400 MHz,
C6D6) 8.17 (d, 2H, ArH), 8.10 (d, 2H, ArH), 7.10–7.00
4.7. (3R,4R,5S)-3,4,5-Trihydroxyazepane 1
A solution of bicyclic compound 9 (12 mg, 83 lmol) in
MeOH (2 mL) was hydrogenated in the presence of
10% Pd on carbon (spatula tip) at room temperature
under atmospheric pressure of hydrogen for 24 h. The
catalyst was removed by filtration through Celite and
the filtrate concentrated in vacuo to give compound 1
(12 mg, 99%) as a colourless oil; [a]D = +23.9 (c 0.65,
H2O); dH (250 MHz, CD3OD) 3.78–3.68 (m, 2H, H-3,
H-5), 3.54 (dd, 1H, J 5.2, J 6.6, H-4), 3.25–3.14 (m,
1H, H-7), 3.06 (m, 2H, 2 · H-2), 2.93 (m, 1H, H-7),
1.96 (m, 2H, 2H-6), dC (62.9 MHz, CD3OD) 80.1(C-
4), 74.1, 72.6 (C-5, C-3), 48.2 (C-2), 44.3 (C-7), 31.2
(C-6); m/z 148 [M+H]+; HRMS found: MH+, 148.0975
(C6H13NO3 requires m/z 148.0973).
(m, 6H, ArH), 5.81(dd, H1 ,
J4,5 4.2, J4,3 9.0, H-4),
5.60 (ddd, 1H, J3,2eq 6.6, J3,2ax 10.0, J4,3 9.0, H-3),
4.67 (dd, 1H, J5,4 4.2, J5,6eq 7.5, H-5), 3.40 (dd, 1H,
J2ax,2eq 13.9, J3,2ax 10.0, H-2ax), 3.28 (dd, 1H, J3,2eq
6.6, J2eq,2ax 13.9, H-2eq), 3.00 (ddd, 1H, J7eq,6eq 11.3,
J7eq,6ax 5.5, J7eq,7ax 16.9, H-7eq), 2.66 (ddd, 1H, J7ax,6eq
4.2, J7ax,6ax 9.2, J7ax,7eq 16.9, H-7ax), 2.04 (ddd, 1H,
J6ax,6eq 14.5, J6ax,7ax 9.2, J6ax,7eq 5.5, H-6ax), 1.64 (m,
1H, J6ax,6eq 14.5, J6eq,7ax 4.2, J6eq,7eq 11.3, J6eq,5 7.5, H-
6eq); dC (100.6 MHz, C6D6) 165.8 (C@O), 165.2
(C@O), 133.0 (CH), 132.9 (CH), 132.8 (CH), 128.5
(CH), 128.4 (CH), 128.3 (CH), 75.5 (C-5), 72.8 (C-4),
67.2 (C-3), 58.6 (C-2), 52.6 (C-7), 29.8 (C-6); m/z 376
[M+Na]+, 354 [M+H]+; HRMS found: MH+,
354.1340 (C20H19NO5 requires m/z 354.1341). Selected
NOE data: irradiation of H-7eq enhances H-7ax
(25.1%), H-6eq (6.1%); irradiation of H-7ax enhances
H-7eq (27.2%), H-3 (6.5%), irradiation of H-6ax en-
hances H-6eq (23.6%), H-7ax (4.1%), H-3 (9.5%); irradi-
ation of H-6eq enhances H-6ax (26.5%), H-7eq (6.4%),
H-5 (8.3%); irradiation of H-5 enhances H-6eq (4.3%),
H-4 (10.0%); irradiation of H-4 enhances H-5 (9.0%),
H-2ax (2.6%); irradiation of H-3 enhances H-2eq
(4.5%), H-7ax (3.4%), H-6ax (6.5%); irradiation of H-
2ax enhances H-2eq (8.9%), H-4 (5.0%); irradiation of
4.8. Enzymatic assays
The enzymes a-glucosidase (rice), b-glucosidase (sweet
almond), a-galactosidase (coffee beans), b-galactosidase
(bovine liver) and a-L-fucosidase (bovine epididymis)
were purchased from Sigma Chemical Co. The rat epi-
didymal fluid was purified from epididymis according
to the method of Skudlarek et al.17 The activity of rice
a-glucosidase was determined using maltose as a sub-
strate at pH 5.0. The released D-glucose was determined
colorimetrically using Glucose B-test Wako (Wako
Pure Chemicals Industries). Other glycosidase activities
were determined using an appropriate p-nitrophenyl gly-
coside as a substrate at the optimum pH of each enzyme.
The reaction was stopped by adding 400 mM Na2CO3.
The released p-nitrophenol was measured spectrometri-
cally at 400 nm.

S. Moutel et al. / Tetrahedron: Asymmetry 16 (2005) 487–491
491
Depezay, J. C.; Dosbaa, I.; Geoffroy, S.; Foglietti, M. J.
Bioorg. Med. Chem. 1997, 5, 519; (h) Johnson, H. A.;
Thomas, N. R. Bioorg. Med. Chem. Lett. 2002, 12, 237; (i)
Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.;
Wang, P. G. Tetrahedron Lett. 2002, 43, 6525; (j) Joseph,
C. C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F.
Tetrahedron 2002, 58, 6907; (k) Fuentes, J.; Gasch, C.;
Olano, D.; Pradera, M. A.; Repetto, G.; Sayago, F. J.
Tetrahedron: Asymmetry 2002, 13, 1743; (l) Painter, G. F.;
Eldridge, P. J.; Falshaw, A. Bioorg. Med. Chem. 2004, 12,
225.
References
1. (a) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stutz, A. E., Ed.; Wiley-VCH: New York, 1999;
¨
(b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645.
2. (a) Compain, P.; Martin, O. R. Curr. Top. Med. Chem.
2003, 3, 541; (b) Compain, P.; Martin, O. R. Bioorg. Med.
Chem. 2001, 9, 3077; (c) Sears, P.; Wong, C.-H. Angew.
Chem., Int. Ed. 1999, 38, 2300.
3. Jakobsen, P.; Lundbeck, J. M.; Kristiansen, M.; Breinholt,
J.; Demuth, H.; Pawlas, J.; Torres Candela, M. P.;
Andersen, B.; Westergaard, N.; Lundgren, K.; Asano,
N. Bioorg. Med. Chem. 2001, 9, 733.
4. (a) Lee, R. E.; Smith, M. D.; Pickering, L.; Fleet, G. W. J.
Tetrahedron Lett. 1999, 39, 8689; (b) Lee, R. E.; Smith, M.
D.; Nash, R. J.; Griffiths, R. C.; McNeil, M.; Grewal, R.
K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J.
Tetrahedron Lett. 1997, 38, 6733.
8. (a) Martin, O. R. In Carbohydrate Mimics: Concepts and
Methods; Chapleur, Y., Ed.; VCH: Weinheim, 1998; pp
´
259; (b) Li, H.; Bleriot, Y.; Chantereau, C.; Mallet,
J.-M.; Sollogoub, M.; Zhang, Y.; Rodriguez-Garcia, E.;
Vogel, P.; Jimenez-Barbero, J.; Sinay, P. Org. Biomol.
¨
Chem. 2004, 2, 1492; (c) Dhavale, D. D.; Markad, S. D.;
Karanjule, N. S.; PrakashaReddy, J. J. Org. Chem. 2004,
69, 4760.
9. Godin, G.; Garnier, E.; Compain, P.; Martin, O. R.;
Ikeda, K.; Asano, N. Tetrahedron Lett. 2004, 45, 579.
10. The following stereoisomers have been reported: 3R,4S,5R
5. (a) Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem.
2003, 3, 525; (b) Evans, G. B.; Furneaux, R. H.;
Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J. Med.
Chem. 2003, 46, 5271; (c) Fedorov, A.; Shi, W.; Kicska,
G.; Fedorov, E.; Tyler, P. C.; Furneaux, R. H.; Hanson, J.
C.; Gainsford, G. J.; Larese, J. Z.; Schramm, V. L.; Almo,
S. C. Biochemistry 2001, 40, 853; (d) Miles, R. W.; Tyler,
P. C.; Furneaux, R. H.; Bagdassarian, C.; Schramm, V. L.
Biochemistry 1998, 37, 8615; (e) Kline, P. C.; Schramm, V.
L. Biochemistry 1993, 32, 13212.
6. Iminosugars: Recent Insights Into Their Bioactivity and
Potential As Therapeutic Agents in Curr. Top. Med. Chem.;
Martin, O. R.; Compain, P., Eds.; Bentham, Neth., 2003,
Vol. 3, issue 5.
7. (a) Paulsen, H.; Todt, K. Chem. Ber. 1967, 100, 512; (b)
Dax, R.; Gaigg, B.; Grassberger, B.; Koelblinger, B.;
(D-lyxo): Andersen, S. M.; Ekhart, C.; Lundt, I.; Stutz,
¨
A. E. Carbohydr. Res. 2000, 326, 22; 3S,4R,5R (D-ribo):
Gallos, J. K.; Demeroudi, S. C.; Stathopoulou, C. C.;
Dellios, C. C. Tetrahedron Lett. 2001, 42, 7497; 3S,4S,5R
(D-xylo): Ref. 7a and Dhavale, D. D.; Chaudhari, V. D.;
Tilekar, J. N. Tetrahedron Lett. 2003, 44, 7321.
11. Moutel, S.; Shipman, M. Synlett 1998, 1333; Dransfield, P.
J.; Moutel, S.; Shipman, M.; Sik, V. J. Chem. Soc., Perkin.
1 1999, 3349.
12. Dong, W.; Jespersen, T.; Bols, M.; Skrydstrup, T.; Sierks,
M. R. Biochemistry 1996, 35, 2788, See also Ref. 3.
13. (a) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98,
863; (b) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48,
5048.
Stutz, A. E. J. Carbohydr. Chem. 1990, 9, 479; (c) Farr, R.
¨
14. Smith, A. L.; Williams, S. F.; Holmes, A. B.; Hughes, L.
R.; Lidert, Z.; Swithenbank, C. J. Am. Chem. Soc. 1988,
110, 8696.
15. Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1
1984, 1689.
16. Kleban, M.; Kautz, U.; Greul, J.; Hilgers, P.; Kugler, R.;
Dong, H.-Q.; Ja¨ger, V. Synthesis 2000, 1027.
17. Skudlarek, M. D.; Tulsiani, D. R. P.; Orgebin-Crist,
M.-C. Biochem. J. 1992, 286, 907.
A.; Holland, A. K.; Huber, E. W.; Peet, N. P.; Weintraub,
P. M. Tetrahedron 1994, 50, 1033; (d) Lohray, B. B.;
Bhushan, V.; Prasuna, G.; Jayamma, Y.; Raheem, M. A.;
Papireddy, P.; Umadevi, B.; Premkumar, M.; Lakshmi, N.
S.; Nayaranareddy, K. Indian J. Chem., Sect. B 1999, 38,
1311; (e) Moris-Varas, F.; Qian, X.-H.; Wong, C.-H. J.
Am. Chem. Soc. 1996, 118, 7647; (f) Qian, X.-H.; Moris-
Varas, F.; Fitzgerald, M. C.; Wong, C.-H. Bioorg. Med.
Chem. 1996, 4, 2055; (g) Le Merrer, Y.; Poitout, L.;