Synthesis and glycosidase inhibitory activity of 1-amino-3,6-anhydro-1-deoxy-d-sorbitol derivatives

Article abstract of DOI:10.1016/j.bioorg.2009.12.002

3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-d-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited β-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1 mM).

Full text of DOI:10.1016/j.bioorg.2009.12.002

Bioorganic Chemistry 38 (2010) 43–47
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Preliminary Communication
Synthesis and glycosidase inhibitory activity of 1-amino-3,6-anhydro-1-deoxy-D-
sorbitol derivatives
c
c
a,
Stéphane Guillarme a, Jean-Bernard Behr b, , Claudia Bello , Pierre Vogel , Christine Saluzzo
*
*
a UCO2M, UMR CNRS 6011, Université du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 09, France
b Institut de Chimie Moléculaire de Reims, UMR CNRS 6229, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims Cedex, France
c Institut de Chimie Moléculaire et Biologique, Ecole Polytechnique Fédérale de Lausanne, BCH, 1015 Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 November 2009
Available online 5 December 2009
3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-D-sorbitol derivatives have been prepared in four steps from
isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have
been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited b-N-acet-
ylglucosaminidase from bovine kidney (82% inhibition at 1 mM).
Keywords:
Isosorbide
Glycosidase
Inhibition
Ó 2009 Elsevier Inc. All rights reserved.
C-glycosides
1. Introduction
myces hygroscopicus var. limoneus) inhibitor of sucrase
(IC50 = 49 nM) [8] and oseltamivir 5 is active against neuramini-
Glycosidase enzymes represent an important class of biocata-
lysts involved in a wide range of anabolic and catabolic reactions
[1]. In turn, specific inhibitors of glycosidases have shown high
promises as probes for function studies of enzymatic events and
as drugs for the treatment of viral or fungal infections [2], cancer
and metabolic disorders such as diabetes [3]. The most potent gly-
cosidase inhibitors known so far are amino-analogues of the natu-
ral carbohydrate substrates, which feature either an endo (in the
ring) or an exo-nitrogen (out of the ring) functionality [4]. Imino-
sugars, the endo-nitrogen analogues, have been the most widely
studied glycosidase inhibitors and a library of hundreds of com-
pounds has been synthetized over the years, which has enabled
the identification of very potent and specific inhibitors through
SAR studies [5]. Deoxynojirimycin (DNJ 1, Fig. 1), the imino-glucose
dase (IC50 in the nanomolar range) and was approved for the treat-
ment of influenza [9]. The inhibitory action of carbohydrate
analogues, which are similar to either intermediates (iminosugars)
or substrates (exo-amino compounds), is attributed particularly to
the potent binding interactions of the nitrogen atom with the car-
boxylate residues present in the active site that are involved in the
catalytic hydrolysis (Fig. 1).
In our search for new series of potent glycosidase inhibitors we
focused on amino-substituted C-furanosides 6, which belong to the
exo-amino sugar analogues family (Fig. 2). Compounds 6 might
also be regarded as oxa-analogues of iminosugars 7a–d which
are potent inhibitors of b-glucosidase (Ki = 13–40
iminosugar 7e, a weak inhibitor of -mannosidase from jack-bean
(IC50 = 3–25 g/mL) [10c]. The supplementary hydroxyl group in
lM) [10] and of
a
l
derivative, is a very potent
a
-glucosidase inhibitor, some opti-
the structure of 6 could virtually induce binding interactions in
the active site, which could counterbalance the loss of the intracy-
clic amino functionnality from 7. Up to now, the potential of such
compounds as glycosidase inhibitors has not been assessed. We
describe herein the synthesis of C-furanosides 6a–e and their bio-
logical evaluation towards 13 different glycosidases.
mized analogues of which have found therapeutic applications to
treat type II diabete or Gaucher’s disease [6]. Much less is known
about the biological potencies of carbohydrate analogues featuring
an exo amino functionality, though some promising results have
been obtained with preliminary models. Thus, amino-substituted
a
- and b-benzyl-C-glucosides 2 (Ki = 11
play potent inhibition against - and b-glucosidase respectively,
the former being as potent as the standard DNJ 1 (Ki = 9 M) [7].
lM) and 3 (Ki = 70 lM) dis-
a
l
2. Results and discussion
In like manner, valiolamine 4 is a potent ‘‘Nature-made” (Strepto-
2.1. Synthesis
* Corresponding authors.
E-mail addresses: jb.behr@univ-reims.fr (J.-B. Behr), christine.saluzzo@univ-lemans.fr
(C. Saluzzo).
Isosorbide is a low-cost biomass derived material that is indus-
trially produced from sorbitol. New interest in the use of isosorbide
0045-2068/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2009.12.002

44
S. Guillarme et al. / Bioorganic Chemistry 38 (2010) 43–47
could be firmly deduced from their analytical data. For each com-
H
N
R1
R2
pound, a signal close to 48–50 ppm was observed in 13C NMR,
which was characteristic of a primary CH2–N carbon.
O
HO
HO
HO
HO
The C-furanosides 10a–e were purified by column chromatog-
raphy over silica gel and isolated in 66–98% yield (Scheme 1).
Deprotection of the isopropylidene group was achieved by treat-
ment of 10a–e with a 1 m solution of HCl. The so-obtained hydro-
chlorides were purified by ion exchange chromatography to yield
fully deprotected aminoalcohols 6a–e.
OH
OH
OH
OH
1
2 : R1=H, R2=CH2NHPh
3 : R1=CH(NH2)Ph, R2=H
HO
2.2. Glycosidase inhibition assay
NH2
OH
O
CO2Et
HO
HO
The inhibitory potencies of compounds 6a–e were assayed to-
AcHN
wards a series of 13 commercial glycosidases (
bovine kidney, -galactosidase from coffee beans, b-galactosidase
from Escherichia coli and from Aspergillus orizae, -glucosidase from
yeast and from rice, b-glucosidase from almonds, amyloglucosidase
from Aspergillus niger, -mannosidase from Jack beans, b-mannosidase
a-L-fucosidase from
OH
NH2
a
a
4
5
a
from snail, b-xylosidase from Aspergillus niger, b-N-acetylglucosa-
minidase from Jack beans and from bovine kidney). The experiments
were performed essentially as previously described [16]. Briefly,
OOC
H
OH
0.01–0.5 unit/mL of enzyme (1 unit = 1 lmol of glycoside hydro-
O
HO
HO
O
O
lyzed/min), preincubated for 5 min at 20 °C with an aqueous solu-
tion of the inhibitor (final concentration 1 mM), and increasing
concentrations of aqueous solution of the appropriate p-nitrophenyl
glycoside substrate buffered to the optimum pH of the enzyme were
incubated for 20 min at 37 °C (45 °C for the amyloglucosidases). The
reactionwasstoppedbytheadditionofa2.5volumeof0.3 Msodium
borate buffer pH 9.8. In a control experiment, the enzyme activity
was assayed in the absence of inhibitor. The p-nitrophenolate
formed was quantified at 405 nm, and the percentage inhibition in
enzyme activity was calculated as follows:
R
OH
O
Fig. 1. Structures of potent glycosidase inhibitors and catalytic hydrolysis of
glycosides.
as a chemical building block has been driven by recent discoveries
of the properties of some derivatives as polymer additives, surfac-
tants or pharmaceuticals [11]. Isosorbide dinitrate (IsordilÒ) is
used pharmacologically as a vasodilator in angina pectoris or in
the treatment of congestive heart failure [12]. In this study, com-
pounds 6a–e could be readily prepared from isosorbide (Scheme
1) [13].
In a first step, isosorbide was reacted with in situ generated iod-
otrimethylsilane (NaI/TMSCl) to afford the pure iodohydrin 8 [14].
The treatment of 8 with sodium hydride gave epoxide 9 in 80%
yield over two steps. In the next step, epoxide 9 was treated with
a series of aliphatic or aromatic amines [15]. When the reaction
was conducted in methanol at 40 °C with a twofold excess of
amine, complete disappearance of the starting epoxide occurred.
Whatever the amine used, the ring-opening was highly regioselec-
tive and only one product could be isolated from the reaction mix-
ture deriving from the attack on the less substituted carbon of the
epoxide. The structures of the so-formed b-aminoalcohols 10a–e
D
Absorbance ðcontrolÞꢀ Absorbance ðtestÞ
D
% Inhibition¼
ꢁ100
D
Absorbance ðcontrolÞ
The results are reported in Table 1. Unlike polyhydroxypyrroli-
dines, the interaction of C-furanoside-like carbohydrate mimics
with glycosidases has scarcely been studied. To our knowledge,
no inhibition data are available in the literature and the results
in Table 1 give a first insight into their potential. Firstly, we found
that the inhibition profile of aminoalcohols 6a–e was significantly
different from that of the corresponding pyrrolidines 7.The N-iso-
propyl derivative 6c was completely inactive against all the tested
enzymes. However, the presence of an aromatic substituent in-
duced some effect in term of strength or selectivity. Thus, com-
pounds 6a,b,d were active against b-galactosidase from
Escherichia coli (42–64% inhibition). The morpholino derivative
6e was active (39%) against
a-
L-fucosidase in a selective manner.
OH
OH
H
H
N
O
N
NRR'
NRR'
NH2
HO
OH
6a-e
HO
OH
HO
OH
7
7e
a : R=H, R'=Bn
b : R=H, R'=Ph
c : R=H, R'=i-Pr
a : R=H, R'=Bn
b : R=H, R'=Ph
c : R=H, R'=
d : R=H, R'=1-napht
d : R,R'=
O
e : R,R'=
O
Fig. 2. Structures of compounds 6 and 7.

S. Guillarme et al. / Bioorganic Chemistry 38 (2010) 43–47
45
OH
O
OH
O
O
O
ii
I
i
O
HO
O
O
O
O
O
isosorbide
8
9
iii
OH
NRR'
iv
6a-e
O
O
10a-e
amine (RR'NH)
yield (10)
BnNH2
PhNH2
i-PrNH2
NH2
66%
75%
77%
a :
b :
c :
72%
d :
NH
98%
O
e :
Scheme 1. Synthesis of compounds 6a–e. Reagents and conditions: (i) TMSCl, NaI, acetone, CH3CN; (ii) NaH, THF (80%, 2 steps); (iii) RR’NH, MeOH, 40 °C (yield given on
Scheme); and (d) HCl 1 M, rt (43–92%).
Surprisingly, in contrast to their analogues 7, none of the tested
compounds had any effect towards the glucose-processing en-
zymes (amyloglucosidase, a- or b-glucosidase). It is interesting to
estingly, the imino analogues 7a–d had no effect on N-acetyl-
glucosaminidase from bovine epididymis A and bovine epididymis
B [10].
note that the ‘‘naked” diamine 11 was also completely inactive
against b-glucosidase, whereas phenyl substituted pyrrolidine 7b
induced 94% inhibition at 1 mM (Fig. 3) [10]. Thus, both the agly-
con part (the aromatic substituent) and the pyrrolidine framework
are required to induce potent inhibition. Release of one of these
two elements led to a dramatical loss in affinity. Finally the naph-
thyl derivative 6d showed promising results towards N-acetylglu-
cosaminidase from bovine kidney (82%). Compound 6a (R = Bn)
displayed also some activity (59%) against the same enzyme. Inter-
3. Conclusion
In conclusion, we have developed a short synthesis of a series of
amino-C-furanosid derivatives as potential glycosidase inhibitors.
The compounds 6a–e have been prepared in four steps starting
from isosorbide, a by-product from the starch industry. Generally,
these aminosugar analogues presented low inhibitory properties
towards glycosidases. However, the naphthyl derivative 6d dis-
played a significant activity towards b-N-acetylglucosaminidase,
a target enzyme for the development of antibacterial agents.
Table 1
Inhibition of glycosidases by compounds 6 (% inhibition at 1 mM concentration).
4. Experimental
6a
6b
6c
6d
6e
a
a
-
L
-fucosidase (bovine kidney)
–
–
–
–
56
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
64
–
–
–
–
–
–
–
–
–
82
39
–
–
–
–
–
–
–
–
–
–
–
–
4.1. General
a-Galactosidase (coffe beans)
b-Galactosidase (escherichia coli)
b-Galactosidase (aspergillus oryzae)
42
–
Reactions were monitored by TLC (Macherey–Nagel Poly-
gramÒsil G/UV254), detection being carried out by spraying with
an alcoholic solution of phosphomolybdic acid or an aqueous solu-
tion of KMnO4 (2%)/Na2CO3 (4%) followed by heating. Column
chromatography was performed on silica gel (Merck, 230–400
mesh). NMR spectra were recorded on a Bruker AC-250 spectrom-
eter (250 MHz for 1H and 62.5 MHz for 13C) or Bruker Avance 400
spectrometer (400 MHz for 1H). Chemical shifts are expressed as
parts per million downfield from the internal standards tetrameth-
ylsilane for D2O or CD3OD solutions. Multiplicities are indicated by
a
a
-Glucosidase, (yeast)
-Glucosidase, (rice)
–
–
–
–
Amyloglucosidase (Aspergillus niger)
b-Glucosidase (almonds)
a-Mannosidase (Jack beans)
–
b-Mannosidase (snail)
b-Xylosidase (Aspergillus niger)
b-N-acetylglucosaminidase (Jack beans)
b-N-acetylglucosaminidase (bovine kidney)
19
–
17
59
a
No inhibition at 1 mM.

46
S. Guillarme et al. / Bioorganic Chemistry 38 (2010) 43–47
OH
H
N
H
N
O
NHPh
NHPh
NH2
HO
OH
6b (0%)
HO
HO
OH
7b (94%)
OH
11 (0%)
Fig. 3. Inhibition potencies of 6b, 7b and 11 towards b-glucosidase.
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), sept
(septuplet) or br s (broadened singlet). Optical rotations were re-
corded on a Perkin–Elmer 343 polarimeter at 20 °C. High resolu-
tion mass spectra were performed on Q-TOF Micro micromass
positive ESI (CV = 30 V).
120.7, 107,5, 82.9, 75.7, 75.2, 74.2, 70.3, 50.3; HRMS (ESI) Calcd
for C16H20NO4 ([M+H]+), 290.1392. Found: 290.1386.
4.2.6. 3,6-Anhydro-1-(morpholino)-1-deoxy-
D-sorbitol 6e
Yield: 88%. [
a]
D = +1.4 (c 0.74, CH3OH); 1H NMR (250 MHz, D2O)
d 4.39 (dt, 1H, J = 4.8, 6.7), 4.25 (t, 1H, J = 4.6), 4.08 (m, 1H), 3.95
(dd, 1H, J = 6.7, 9.0), 3.82–3.67 (m, 6H), 2.55–2.32 (m, 6H) ; 13C
NMR (62.5 MHz, CDCl3) d 81.6, 70.1, 69.9, 69.0, 65.8, 2 ꢁ 65.0,
59.6, 2 ꢁ 51.9; Calcd for C10H20NO5 ([M+H]+), 234.1341. Found:
234.1345.
4.2. Preparation of 3,6-anhydro-
D-sorbitol derivatives
4.2.1. General procedure
A solution of epoxide 8 (1 equiv) and amine (2 equiv) was
heated at 40 °C in methanol (c = 0.2 M) for 16 h. The solvent was
then removed and the crude product was purified by column chro-
matography (eluent: CH2Cl2/MeOH (95/5)). An aqueous solution of
hydrogen chloride (1 m concentration) was added to the residue
and the solution was stirred overnight. Evaporation of the solvents
gave a crude material which was subjected to ion exchange chro-
matography (Dowex 50WX-8 resin). Elution with 0.8 M NH4OH
gave pure 6 as a yellowish oil.
Acknowledgments
The authors would like to thank the Ministère de la Recherche
and the CNRS for their financial support and M. Lorilleux, V. Guidal
and P. Guillé for their technical assistance. We also thank the Swiss
National Science Foundation for financial support.
References
4.2.2. 3,6-Anhydro-1-(benzylamino)-1-deoxy-D-sorbitol 6a
Yield: 81%. ½a 2D0
ꢂ
= ꢀ11.8 (c 0.52, H2O); 1H NMR (400 MHz, D2O)
[1] A. Varki, Glycobiology 3 (1993) 97–130.
[2] (a) C. Lazar, D. Durantel, A. Macovei, N. Zitzmann, F. Zoulim, R.A. Dwek, N.
Branza-Nichita, Antiviral Res. 76 (2007) 30–37;
d 7.35–7.10 (m, 5H), 4.40 (dt, 1H, J = 6.7, 4.8), 4.19 (dd, 1H, J = 4.6,
4.5), 4.02 (ddd, 1H, J = 8.5, 6.6, 3.7), 3.94 (dd, 1H, J = 9.0, 6.7), 3.88–
3.76 (m, 3H), 3.68 (dd, 1H, J = 9.0, 6.6), 2.80 (dd, 1H, J = 12.7,
3.7 Hz), 2.55 (dd, 1H, J = 12.7, 8.5); 13C NMR (62.5 MHz, D2O) d
139.1, 129.1, 129.0, 127.9, 82.5, 71.7, 71.3, 70.5, 69.2, 52.6, 50.3;
HRMS (ESI) Calcd for C13H20NO4 ([M+H]+), 254.1392. Found:
254.1392.
(b) I. Robina, A.J. Moreno-Vargas, A.T. Carmona, P. Vogel, Curr. Drug Metab. 5
(2004) 329–361;
(c) P. Greimel, J. Spreitz, A.E. Stütz, T.M. Wroddnigg, Curr. Top. Med. Chem. 3
(2003) 512–523;
(d) J.-B. Behr, Curr. Med. Chem. (Anti Infective Agents) 2 (2003) 173–189;
(e) I. Gautier-Lefebvre, J.-B. Behr, G. Guillerm, M. Muzard, Eur. J. Med. Chem. 40
(2005) 1255–1261;
(f) A. Mehta, N. Zitzmann, P.M. Rudd, T.M. Block, R.A. Dwek, FEBS Lett. 430
(1998) 17–22.
4.2.3. 3,6-Anhydro-1-(phenylamino)-1-deoxy-D-sorbitol 6b
[3] (a) C. Kuriyama, O. Kamiyama, K. Ikeda, F. Sanae, A. Kato, I. Adachi, T.
Imahori, H. Takahata, T. Okamoto, N. Asano, Bioorg. Med. Chem. 16 (2008)
7330–7336;
Yield: 43%. ½a 2D0
ꢂ
= ꢀ15.9 (c 0.71, CH3OH); 1H NMR (400 MHz,
D2O) d 7.30–7.24 (m, 2H), 6.88–6.81 (m, 3H), 4.37 (dt, 1H, J = 6.6,
4.8), 4.28 (dd, 1H, J = 4.6, 4.5), 4.05 (ddd, 1H, J = 8.6, 6.5, 3.6),
3.95 (dd, 1H, J = 9.0, 6.7), 3.87 (dd, 1H, J = 6.4, 4.3), 3.69 (dd, 1H,
J = 9.0, 6.7), 3.40 (dd, 1H, J = 13.6, 3.6 Hz), 3.10 (dd, 1H, J = 13.6,
8.6); 13C NMR (62.5 MHz, D2O) d 147.9, 130.0, 119.5, 115.1, 81.9,
71.7, 71.5, 70.5, 68.7, 50.1, 46.9; HRMS (ESI) Calcd for C12H18NO4
([M+H]+), 240.1236. Found: 240.1240.
(b) H. Fiaux, F. Popowycz, S. Favre, C. Schütz, P. Vogel, S. Gerber-Lemaire, L.
Juillerat-Jeanneret, J. Med. Chem. 48 (2005) 4237–4246;
(c) Y. Nishimura, Curr. Top. Med. Chem. 3 (2003) 575–591;
(d) P.S. Johnson, H.E. Lebovitz, R.F. Coriff, D.C. Simonson, P. Raskin, C.L.
Munera, J. Clin. Endocrinol. Metab. 83 (1998) 1515–1522;
(e) A. Mitrakou, N. Tountas, A.E. Raptis, R.J. Bauer, H. Schulz, S.A. Raptis,
Diabetic. Med. 15 (1998) 657–660;
(f) R.J. Bernaki, W. Korytnyk, Cancer Metast. Rev. 4 (1985) 81–101.
[4] E.B. de Melo, A. da Silveira Gomez, I. Carvalho, Tetrahedron 62 (2006) 10277–
10302.
[5] A.E. Stütz (Ed.), Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond, Wiley-VCH, Weinheim, Germany, 1999.
[6] (a) B.G. Winchester, Tetrahedron: Asymmetr. 20 (2009) 645–651;
(b) P. Compain, O.R. Martin (Eds.), Iminosugars: From Synthesis to Therapeutic
Applications, Wiley-VCH, Weinheim, Germany, 2007.
4.2.4. 3,6-Anhydro-1-(isopropylamino)-1-deoxy-D-sorbitol 6c
Yield: 92%. ½a 2D0
ꢂ
= ꢀ9.7 (c 0.7, H2O); 1H NMR (400 MHz, D2O) d
4.39 (dt, 1H, J = 6.7, 4.8), 4.24 (dd, 1H, J = 4.5), 3.97–3.92 (m, 2H),
3.81 (dd, 1H, J = 6.4, 4.3), 3.68 (dd, 1H, J = 9.0, 6.6), 2.88 (sept, 1H,
J = 6.3), 2.81 (dd, 1H, J = 12.7, 3.6 Hz), 2.63 (dd, 1H, J = 12.6, 8.7);
13C NMR (75 MHz, D2O) d 82.6, 71.7, 71.4, 70.5, 69.3, 48.5, 48.4,
21.5, 21.3; HRMS (ESI) Calcd for C9H20NO4 ([M+H]+), 206.1392.
Found: 206.1387.
[7] (a) H. Dietrich, R.R. Schmidt, Carbohydrate Res. 250 (1993) 161–176;
(b) R.R. Schmidt, H. Dietrich, Angew. Chem. Int. Ed. 30 (1991) 1328–1329.
[8] X. Chen, Y. Fan, Y. Zheng, Y. Shen, Chem. Rev. 103 (2003) 1955–1977.
[9] J.-J. Shie, J.-M. Fang, C.-H. Wong, Angew. Chem. Int. Ed. 47 (2008) 5788–
5791.
[10] A.T. Carmona, F. Popowycz, S. Gerber-Lemaire, E. Rodriguez-Garcia, C. Schütz,
P. Vogel, I. Robina, Biorg. Med. Chem. 11 (2003) 4897–4911;
See also (a) S. Gerber-Lemaire, F. Popowycz, E. Rodriguez-Garcia, A.T. Carmona
Asenjo, I. Robina, P. Vogel, Chem. Biochem. 3 (2002) 466–470;
(b) F. Popowycz, S. Gerber-Lemaire, E. Rodriguez-Garcia, A.T. Carmona Asenjo,
I. Robina, P. Vogel, Bioorg. Med. Chem. Lett. 11 (2001) 2489–2493;
(c) R.A. Farr, A.K. Holland, E. Huber, N.P. Peet, P.M. Weintraub, Tetrahedron 50
(1994) 1033–1044.
4.2.5. 3,6-Anhydro-1-(naphthylamino)-1-deoxy-D-sorbitol 6d
Yield: 76%. ½a 2D0
ꢂ
= ꢀ5.1 (c 0.59, CH3OH); 1H NMR (400 MHz,
CD3OD) d 8.0–7.92 (m, 1H), 7.76–7.70 (m, 1H), 7.42–7.63 (m,
2H), 7.30–7.26 (m, 1H), 7.16 (d, 1H, J = 8.2), 6.69 (d, 1H, J = 7.6),
4.30–4.22 (m, 3H), 4.0–3.88 (m, 2H), 3.82–3.76 (m, 1H), 3.55 (dd,
1H, J = 12.7, 4.9), 3.33 (dd, 1H, J = 12.7, 7.1); 13C NMR (75 MHz,
D2O) d 145.9, 137.0, 131.4, 129.3, 128.6, 127.6, 126.5, 122.8,
[11] G. Flèche, M. Huchette, Starch 38 (1986) 26–30.
[12] (a) G.R.J. Thatcher, Curr. Top. Med. Chem. 5 (2005) 597–601;
(b) K.S. Ravikumar, S. Chadrasekaran, Synthesis (1994) 1032–1034;

S. Guillarme et al. / Bioorganic Chemistry 38 (2010) 43–47
47
(c) R. Seemayer, N. Bar, M.P. Schneider, Tetrahedron: Asymmetr. 3 (1992)
1123–1126;
[14] (a) S. Ejjiyar, C. Saluzzo, R. Amouroux, M. Massoui, Tetrahedron Lett. 38 (1997)
1575–1576;
(d) M. Volger, U. Koert, K. Harms, D. Dorsch, J. Gleitz, P. Raddatz, Synthesis
(2004) 1211–1228.
[13] S. Guillarme, T.X.M. Nguyen, C. Saluzzo, Tetrahedron: Asymmetr. 19 (2008)
1450–1454;
(b) S. Ejjiyar, C. Saluzzo, R. Amouroux, Org. Synth. 77 (2000) 91;
(c) S. Ejjiyar, C. Saluzzo, M. Massoui, R. Amouroux, N. Terry, A.W. Coleman, J.
Phys. Org. Chem. 14 (2001) 1–10.
[15] Similar reactions presented by: I. Lundt, R. Madsen, S. Al Daher, B. Winchester,
Tetrahedron 50 (1994) 7513–7520.
[16] A. Brandi, S. Cicchi, F.M. Cordero, B. Frignoli, A. Goti, S. Picasso, P. Vogel, J. Org.
Chem. 60 (1995) 6806–6812.
For other routes to compounds of type 6 and stereoisomers see:(a) J.C. Norrild,
C. Pedersen, I. Soetofte, Carbohydr. Res. 297 (1997) 261–272;
(b) J.C. Norrild, C. Pedersen, J. Defaye, Carbohydr. Res. 291 (1996) 85–98.