Synthesis of 4-amino-4,5-dideoxy-L-lyxofuranose derivatives and their evaluation as fucosidase inhibitors

Article abstract of DOI:10.1016/j.carres.2011.03.030

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L- lyxofuranose) was synthesised from d-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur

Full text of DOI:10.1016/j.carres.2011.03.030

Carbohydrate Research 346 (2011) 1202–1211
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of 4-amino-4,5-dideoxy-L-lyxofuranose derivatives and their
evaluation as fucosidase inhibitors
⇑
Carine Chevrier, Didier Le Nouën, Albert Defoin , Céline Tarnus
Laboratoire de Chimie Organique et Bioorganique, FRE 3253, École Nationale Supérieure de Chimie de Mulhouse, Université de Haute-Alsace, 3, rue Alfred Werner,
F-68093 Mulhouse Cédex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The nitrone
from -ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe
two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar
inhibitor 4-amino-4,5-dideoxy- -lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the
related 1,2,5,6-tetradeoxy-2,5-imino- -altroheptonic ester 2a, acid 2b and the corresponding heptitol
2c. The new iminosugars have been evaluated for their inhibitory activity against -fucosidase from
4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised
Received 12 January 2011
Received in revised form 10 March 2011
Accepted 16 March 2011
D
L
Available online 24 March 2011
L
a
-L
Keywords:
Aminolyxose
Aminosugars
Fucosidase inhibition
bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar
3 (Ki = 8 vs 10 nM).
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
as of derivatives possessing an N–O bond has been tested against
a-L-fucosidase from bovine kidney. A preliminary communication
Among sugars, the
L-fucose is the most hydrophobic one and
of these results has already been published.14
has for this reason a particular importance in mammalian oligosac-
charides.1 For instance, the fucose moiety in sialyl Lewis-x tetra-
saccharide is essential for the adhesion of leucocytes to the
endothelial membrane of the blood vessels, which is the early
stage of the inflammatory process. Inhibition of fucoside biosyn-
thesis offers a chance to influence the inflammation process.2–4
2. Results and discussion
2.1. Synthesis of the nitrone 4
The synthesis of the nitrone 4 from D-ribose required two trans-
Great attention was focussed on the synthesis of
logues as inhibitors of
-fucosidase5 or fucosyl-transferase.3 Some
derivatives of -fucosi-
-fuconojirimycin 16–10 are very potent
L-fucose ana-
formations, the first one was the elimination of the 5-hydroxyl
group, the second one the formation at the anomeric position of
an oxime followed by nucleophilic cyclisation.
L
L
a-L
dase inhibitors and even subnanomolar ones were obtained with
a C-anomeric binding substituent.8c,d Inhibitory properties of five-
membered ring analogues are not well documented, although under
2.1.1. Synthesis of the 5-deoxyribose 10
The O-protected 5-deoxyribose 10 had already been synthesised
current investigation. 1,4-Imino-
L
-lyxitol derivatives 211 or iso-
L-fucosidase or fucosyl-transferase
by Bols15 in three steps and ca. 50% yield from
D
-ribose by
mers11a,f,12 were found to act as
inhibitors (Scheme 1).
A first synthesis of the 4-amino-4,5-dideoxy-L-lyxose (3), a
HO
potent nanomolar
a-L-fucosidase inhibitor, has been presented
NH
NH
OH
OH
by Wong et al.11b in 1995. We later reported an alternative synthe-
sis based on an asymmetric hetero-Diels–Alder.13 In the present
work we describe a third approach to this amino-sugar using the
HO
R
HO
OH
1
2
O-protected nitrone 4 in the L-lyxose series as an intermediate. In
O
addition, this nitrone leads to the synthesis of some C-glycosides
in the 1,2,5,6-tetradeoxy-2,5-imino-heptonic and heptitol series
2a–c. The inhibitory efficiency of the new imino-sugars as well
N
N
HO
O
O
OH
4
3
⇑
Corresponding author. Tel.: +33 (0)3 89 33 68 64; fax: +33 (0)3 89 33 68 75.
E-mail address: Albert.Defoin@uha.fr (A. Defoin).
Scheme 1.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.030

C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
1203
hydrogenolysis of a 5-iodo derivative. We describe below an
alternative synthesis starting from the two anomers of the benzyl
moderate yield. Subsequent oxidation with mercuric oxide gave a
quantitative mixture of the two isomeric nitrones 13 and 4 in an
80% and 20% yield, respectively, the desired nitrone 4 being the
minor isomer.
2,3-O-isopropylidene-
-ribose.
The O-protection of the
D-ribosides 5a
and 5b16 in 53% yield from
D
D-ribose was achieved in two steps
The second method, developed by Holzapfel25 in the glucose
series, was applied with some changes. Similar methods have also
been described.23,26 The protected 5-deoxy ribose 10 was trans-
formed into its oxime 14 under conditions described in lit.16 in good
yield. The oxime function was then O-silylated with ClSiMe2tBu in
pyridine into the derivative 15 as 50:50 E/Z mixture in a 67% yield.
Mesylation of the 4-hydroxyl group gave then the mesylate 16,
which was rather unstable but isolable, in contrast to a simpler ana-
logue.23 Its desilylation with fluoride ion in the presence of triethyl-
amine led to a spontaneous cyclisation (with nucleophilic attack of
the oxime N- or O-atom, respectively) into a mixture of the expected
five-membered ring nitrone 4 and of the six-membered ring dihy-
dro-oxazine 17. Minor by-products (1–2%) were isolated, the nitrile
18 resulting from an elimination of the O-silyl group as already ob-
served in a similar reaction,23 and the amide 19 stemming from an
isomerisation. The proportions of the nitrone 4 and the oxazine 17
were very dependent on the reaction conditions: deprotection in
acetonitrile at rt, 50 or 80 °C with CsF or anhydrous nBu4F led only
to a 50:50 mixture. The best conditions were with 1.3 equiv of crys-
tallised nBu4Fꢀ3H2O and triethylamine at 80 °C, with formation of a
90:10 mixture of 4 and 17, respectively, which was easily resolved
by chromatography. The nitrone 4 was then obtained with ca. 40%
yield from the protected deoxyribose 10.
according to Vasella’s method as separable mixture of the crystal-
line b-anomer 5b (ca. 55%) and the not described amorphous
a-anomer 5a (ca. 15%). More direct one pot methods in BnOH/ace-
tone gave the same result17 (or a disappointing transformation18).
In order to introduce a methyl group, two methods were ap-
plied (Scheme 2). Preliminary replacement of the 5-hydroxyl group
by bromine (with 5b only) was achieved best with PPh3 and tetrab-
romomethane19 to give the 5-bromo derivatives 6b in essentially
quantitative yield. Use of PPh3 and bromine20 led to a capricious
reaction (33–73% yield) with partial loss of the acetonide group.
Attempts to reduce the 5-bromine atom either by catalytic hydro-
genation over 5% Pd/C in the presence of a base (3 equiv aqueous
KOH) at 50 °C20 or by reduction with AlLiH4 in ether21 provided
the expected 5-deoxy-ribose 9b in only moderate yield (60%).
An attempt to reduce 6b by hydrogenolysis over Raney-nickel
led to the O-protected 5-deoxyribitol 7 with elimination of both
the bromine atom and the anomeric benzyl group and concomitant
reduction of the formed aldehyde group.
A second method for elimination of the 5-hydroxyl group was
then used with better results. Alcohols 5
a
a
and 5b were easily
and 8b, and subse-
mesylated into the respective mesylates 8
22
quent reductive elimination with AlLiH4 provided the respective
5-deoxy derivatives 9 and 9b with good yield.
a
Benzyl deprotection of the anomeric position proved difficult.
Setting up a classical hydrogenolysis of 9b over Pd/C in ethanol
with 1–10% acetic acid gave unsatisfactory results. Finally, hydrog-
enolysis with 5% formic acid in ethanol at 30 °C led to the desired
2.1.3. Amino-sugar preparation and O-deprotection
The action of SO2 on the nitrone 4 in aqueous solution for 1 day
at room temperature induced a multi-step reaction leading to the
known amino-L-lyxose-1-sulfonic acid 20: reduction of the N–O
5-deoxyribose 10 as 10:90 mixture of anomers
yield (96%). It is important to eliminate any sulfurated compounds;
purification of 9b was achieved by sublimation and of 9 by treat-
ment with a little H2O2 as described in the experimental part. The
a
and b in excellent
bond, hydrolysis of the acetonide moiety and addition onto the
intermediary amino-sugar 3 (Scheme 4). The crystalline sulfite ad-
duct 20 was isolated by precipitation with ethanol in a 62% yield;
its physical data were identical with those in the literature.13 This
a
overall yield of deoxyribose 10 from 5
a
and 5b amounted to 59%
adduct 20 is assumed to be the
a-anomer because of the similar
and 80%, respectively.
values of J(1,2) and J(2,3) with those of the corresponding unme-
thylated homologue in the L
-erythrose series.27 The preparation
2.1.2. Nitrogen insertion
of the amino-sugar 3 by elimination of SO2 with baryta13 has al-
ready been described.
The O-deprotection of the nitrone 4 and the trihydro-oxazine 17
was carried out in 6 N HCl in methanol to give the corresponding
diols 21 and 22 (Scheme 4). The oxazinane 24 was obtained from
17 by reduction of the oxime function with NaBH3CN in acetic
acid28 into 23 and subsequent hydrolysis as above.
The formation of the nitrone functionality was achieved follow-
ing two methods as presented in the Scheme 3. Under Brandi’s con-
ditions23,24 the ribitol 7 was cyclised by double nucleophilic
substitution from the dimesylate 11 with hydroxylamine in boiling
triethylamine. In this case the reaction required the presence of an
added base as DBU; N-hydroxypyrrolidine 12 was obtained with
1. BnOH, HCl
Br
HO
2. Acetone,
OH
O
O
O
OBn
OBn
FeCl
3
PPh , CBr
Ni-Raney
OH
3
4
D-ribose
for 5β, quant.
O
6β
O
O
O
O
EtOH
aq. KOH
75%
7
5α (
5β ( OBn) 50-60%
OBn) 15-20%
AlLiH
4
or H /Pd-C
2
MsCl, NEt
3
aq N KOH, EtOH
(60%)
MeO SO
2
4
O
1
O
O
OH
OBn
H /Pd-C
2
OBn
5
AlLiH
4
3
O
2
EtOH
O
O
Et O
2
O
O
O
5% HCO H
2
59% from 5α
96% from 9β
10(α+β)
9α (quant)
9β (92%)
8α (quant)
8β (91%)
Scheme 2.

1204
C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
NH OH.HCl
pyridine DBU
85 °C
2
O
N
O
N
OH
N
1
OR
O
4
5
5
1
HgO
OR
2
+
3
O
2
4
3
quant.
45%
O
O
O
O
O
O
80/20
7 R = H
13
4
12
MeSO Cl
2
NEt , 30%
11 R = SO Me
2
3
O
N
1
2
O
N
OR'
N
OH
O
OR
OMs
CN
3
NH OH
CONH
2
2
10
+
+
+
5
O
4
O
(-)
EtOH/H O
2
F
, 80°C
O
O
O
O
O
O
O
96%
MeCN
ClSiMe tBu
2
Pyridine 67%
MsCl, quant.
14 R = R' = H
15 R = H R' = SiMe
16 R = Ms R' = SiMe
19 (1%)
4 (60%)
18 (1%)
17(6%)
t
Bu
2
t
Bu
2
Scheme 3.
ester 27b with AlLiH4 gave the alcohol 28. The fucose analogues
were obtained by total deprotection of the ester 27a and of the
alcohol 28: hydrolysis with 6 N HCl of the acetonide moiety, fol-
lowed by N-deprotection by hydrogenolysis over Pd/C, led to pyr-
rolidinediols ester hydrochloride 2aꢀHCl and, after basic treatment,
to the alcohol 2c, respectively. The phenyl ester 27b under these
conditions produced the acid 2b. Hydrolysis of the adduct 26b gave
the bicyclic diol 29.
A simpler synthesis of the alcohol 2c was effected by direct
hydrogenolysis of the bicyclic adduct 26a over Raney-nickel with
cleavage of the N–O bond and reduction of the formed aldehyde
function. A subsequent acidic hydrolysis of the acetonide moiety
led to the triol 2c as crystalline hydrochloride in moderate yield.
Ba(OH)
2
H
13
N
SO H
3
quant. ref
3
HO
OH
20
SO , H O
2
2
75%
O
N
O
N
HCl 6 N
MeOH
HO
OH
quant
O
O
21
4
HCl 6 N
MeOH
O
O N
N
2.3. Fucosidase inhibition
81%
HO
OH
O
O
The new C-a-lyxosides were evaluated against a-L-fucosidase
from bovine kidney and the results are reported in the Table 1 in
comparison with the known amino-sugar 313 (Scheme 5). All
inhibitors were competitive. These results deserve two comments:
Nitrone 21 and oxazines 22, 24 were poor inhibitors as are other
similar compounds33 probably because of their weak basicity
which reduced the bonding in the enzyme active site. On the other
22
17
NaBH CN, AcOH
3
44%
HCl 6 N
MeOH
O NH
O NH
HO OH
quant.
O
O
hand, among the C-a-substituted compounds, the bicyclic one 29
and the amino-heptonic acid and ester 2a,b were only micromolar
inhibitors. In contrast the amino-heptitol 2c14 was as potent a
fucosidase inhibitor as the amino-sugar 3. These results point out
to the importance of a hydroxyl group at the anomeric position
for the recognition of the inhibitor by the enzyme. In this present
24
23
Scheme 4.
case, the C-a-hydroxyethyl group has nearly the same effect as
2.2. Cycloaddition reaction and transformations
the anomeric hydroxyl group for the aminosugar 3 or as the
C-hydroxymethyl group for known analogues.11i,j
1,3-Dipolar cycloaddition29a,b appeared to be an easy method to
functionalise nitrones and the use of an enol ether as dipolarophile
permitted the addition of an acetate chain following a rearrange-
ment.30a,b,31 As dipolarophiles, we have used the commercial ethyl
enol ether 25a and the known phenyl analogue 25b32 whose syn-
thesis was improved.
3. Conclusion
Starting from D-ribose, we have worked out the synthesis of the
nitrone 4 of 4-amino-4,5-dideoxy-2,3-O-isopropylidene-L-lyxose in
The cycloaddition reaction of nitrone 4 with 25a,b was achieved
in tetrachlorethane (16 h at 50 °C) and gave exclusively the ad-
ducts 26a,b in good yield. The regioselectivity was concluded from
the X-ray structure of the phenoxyl adduct 26b14 in agreement
with the literature data.30a It corresponds to an exo-approach of
the dipolarophile from the less bulky side.
The opening of the oxazolidine ring of the adducts 26a,b
occurred as in lit.30,31 by N-benzylation with benzyl bromide in
chloroform, followed by a thermal rearrangement at 50 °C, and
led easily to the esters 27a,b. Then the reduction of the phenyl
Table 1
Inhibition constants for the pyrrolidines 2a,b,c, 21, 29 and oxazines 22, 24 against
fucosidase from bovine kidney (Ki in
a-L-
l
M) in comparison with amino-L-lyxose 313
Compounds
Ki ( -fucosidase)
3
21
22
24
29
2a
2b
2c
0.008c
a
-
L
0.01a
50b
300b
225b
5.3
0.7
10
a
b
c
Ref. 13. Ki = 0.16
IC50
Ref. 14.
lM in Ref. 11b.
.

C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
1205
OR
OR
Bn
N
Bn
N
OH
2
O
N
CO R
1. BnBr
2. 50°C
2
3
AlLiH
89%
4
25a,b
H
5
O
4
O
O
O
O
O
C H Cl
4
2
2
for 27b
50 °C
a R= Et
b R= Ph
26a (85%)
b (quant.)
27a (35%)
b (67%
28
1. 6 N HCl MeOH
2. H /Pd-C, EtOH
3. Amberlite IR-120
for 26a
1. H /Raney-Ni,
6 N HCl
MeOH, quant
2
for 26b
2
EtOH
for 2b and 2c
OPh
2. 6 N HCl EtOH
1'
OH
2'
H
N
H
N
O
N
CO R
2
2
3
5
2c (46%)
H
4
HO
OH
HO
OH
HO
OH
2a.HCl R = Et (21%)
b R = H (62%)
2c (quant.)
29
Scheme 5.
a 22% overall yield. This compound has been easily converted in
the 4-amino-4,5-dideoxy- -lyxose (3), a known nanomolar inhibi-
tor (Ki = 10 nM) of -fucosidase from bovine kidney. The dipolar
cycloaddition of the nitrone 4 with ethyl vinyl and phenyl vinyl
ethers gave bicyclic oxazolidines which were transformed into
aqueous 1 M CO3Na2 solution, then brine. After evaporation of
the solvent, iPr2O was added and the mixture left to crystallise at
0 °C for 16 h. 5b (50–60%) was isolated by filtration and washing
with iPr2O. The mother liquors were resolved by FC (CH2Cl2, then
L
a-L
Et2O) to give 5b (2–3%) and 5a
(15–20%). The methods of Duvold17
the 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptitol (2c), another
or Karpiesuk18 gave 53% or 23% of 5b, respectively, after crystallisa-
tion in iPr2O.
nanomolar inhibitor (Ki = 8 nM) of this enzyme. The heptonic acid
derivatives 2a,b are micromolar inhibitors, but the compounds
bearing a N–O bond are only submillimolar ones.
Anomer 5b: colourless crystals: mp 106–108 °C (iPrOH),
½
a 1D8
ꢂ
= ꢁ96 (c 1.0, CHCl3) [lit.16: mp 104 °C, [
D = ꢁ94.4 (c 1.08,
a]
CHCl3); lit.18: mp 104–105 °C, ½a 2D0
ꢂ
= ꢁ75.8 (c 1.8, CHCl3); lit.17
:
mp 108–110 °C, ½a D25
ꢂ
= ꢁ113 (c 1.0, CHCl3)]. 1H NMR (250 MHz,
4. Experimental
CDCl3): d 1.32, 1.49 (2s, 2 ꢃ 3H, CMe2); 3.17 (dd, 1H, OH-5); 3.65
(ddd, 1H, Hb-5); 3.72 (ddd, 1H, Ha-5); 4.46 (t, 1H, H-4); 4.57 (d,
1H, J = 11.5 Hz, CHPh); 4.67 (d, 1H, H-2); 4.77 (d, 1H, J = 11.5 Hz,
CHPh); 4.86 (d, 1H, H-3); 5.18 (s, 1H, H-1); 7.35 (m, 5Har);
J(1,2) = 0, J(2,3) = 6.0, J(3,4) = ca. 0.5, J(4,5a) = 2.4, J(4,5b) = 3.6,
J(5a,5b) = 12.5, J(OH,5a) = 3.4, J(OH,5b) = 10.0; similar data as in
lit.16,18 13C NMR (62.9 MHz, CDCl3): same values as in lit.16
4.1. General methods
Flash chromatography (FC): silica gel (Merck 60, 230–400
mesh). TLC: Al-roll silica gel (Merck 60, F254). Mp: Kofler hot bench,
corrected. IR spectra (m
in cmꢁ1): Nicolet 405 FT-IR or Perkin–Elmer.
[a]D: Schmidt-Haensch Polartronic Universal or Perkin–Elmer 341 LC
Anomer 5
a
: colourless resin, ½a D18
ꢂ
= +56 (c 1.0, CHCl3). IR
polarimeter. 1H and 13C NMR (250 or 400 MHz, 62.9 or 100.6 MHz,
respectively) spectra: Bruker AC-F 250 or Bruker Avance 400,
tetramethylsilane (TMS) or natrium (D4)-trimethylsilylpropionate
(D4-TSP) in D2O (1H NMR) and CDCl3, or (in D2O) dioxane [d
(CDCl3) = 77.0, in D2O d (dioxane) = 67.4 with respect to TMS]
(CHCl3): 3600, 2995, 2930, 1453, 1380, 1370, 1260, 1160, 1140,
1095, 1080, 1018, 855 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.37,
.
1.56 (2s, 2 ꢃ 3H, CMe2); 1.78 (dd, 1H, OH-5); 3.72 (ddd, 1H, Hb-
5); 3.84 (ddd, 1H, Ha-5); 4.24 (q, 1H, H-4); 4.63 (d, 1H,
J = 11.2 Hz, CHPh); 4.67 (m, 1H, H-2), 4.69 (dd, 1H, H-3); 4.85 (d,
1H, J = 11.2 Hz, CHPh); 5.10 (d, 1H, H-1); 7.25–7.40 (m, 5Har);
J(1,2) = 3.7, J(2,3) = 7.0, J(3,4) = 2.6, J(4,5a) = 3.2, J(4,5b) = 3.7,
J(5a,5b) = 12.0, J(5a,OH) = 4.7, J(5b,OH) = 7.8 Hz. 13C NMR
(100 MHz, CDCl3): d 25.8, 25.9 (CMe2); 62.5 (CH2(5)); 69.5 (CH2Ph);
80.3 (C(3)); 80.9 (C(2)); 81.7 (C(4)); 100.7 (C(1)); 115.5 (CMe2);
127.0, 127.5, 128.2 (3Car); 137.7 (Car-s). Anal. Calcd for C15H20O5
(280.31): C, 64.27; H, 7.19. Found: C, 64.0; H, 7.1.
(
13C NMR) as internal references; d in ppm and J in Hz. High reso-
lution MS were measured on a Waters Micromass Q-Tof Ultima API
spectrometer in Basilea Pharmaceuticals, Basel or in Service de
Spectrometrie de masse, ECPM, Strasbourg. Microanalyses were
carried out by the Service Central de Microanalyses du CNRS,
F-69390 Vernaison.
Reagents and solvents: Raney-nickel aqueous suspension, 5% Pd/
C were obtained from Fluka. Usual solvents were freshly distilled,
dry EtOH and MeOH distilled over Mg/MgI2, dry THF over Na and
benzophenone, dry Et2O was distilled and stored over Na, CH2Cl2
was distilled over P2O5 and kept over Na2CO3. NEt3 and tetrachlo-
roethane (C2Cl4H2) were distilled before use.
4.2.2. Benzyl 5-bromo-5-deoxy-2,3-O-isopropylidene-b-
ribofuranoside (6b)
D-
To a solution of 5b (5.0 g, 18 mmol) in dry CH2Cl2 (30 mL) at 0 °C
were added under Ar CBr4 (13.3 g, 0.04 mol, 2 equiv) and PPh3
(10.5 g, 0.04 mol, 2 equiv). The solution was stirred at rt for 5 h,
then diluted in Et2O (200 mL) to precipitate OPPh3 which was fil-
tered off. The solvent was evaporated and the residue purified by
FC (Cyclohexane/AcOEt 9:1) to give 6b (6.1 g, quant.), to store at
0–5 °C.
4.2. D-Ribose derivatives
4.2.1. Benzyl 2,3-O-isopropylidene-
and b (5 , 5b)
D-ribofuranoside, anomers a
a
6b: yellowish resin, ½a D20
= ꢁ84 (c 1.0, CHCl3), Rf = 0.7 (Cyclohex-
ꢂ
The Vasella procedure16 was essentially followed, the final
work-up was modified: neutralisation of FeCl3 was carried out
with aqueous 1 M CO3Na2 solution, acetone was evaporated and
the residue extracted with AcOEt, the organic phase washed with
ane/AcOEt 7:3). 1H NMR (250 MHz, CDCl3): d 1.33, 1.49 (2s, 2 ꢃ 3H,
CMe2); 3.38 (t, 1H, Hb-5); 3.47 (dd, 1H, Ha-5); 4.44 (dd, 1H, H-4);
4.48 (d, 1H, J = 11.5 Hz, CHPh); 4.72 (d, 1H, H-2); 4.74 (d, 1H,

1206
C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
J = 11.5 Hz, CHPh); 4.79 (d, 1H, H-3); 5.22 (s, 1H, H-1); 7.33 (m,
5Har); J(1,2) = 0, J(2,3) = 6.0, J(3,4) = ca. 0, J(4,5a) = 6.1,
J(4,5b) = 9.7, J(5a,5b) = 10.1 Hz. 13C NMR (62.9 MHz, CDCl3): d
24.8, 26.3 (CMe2); 32.6 (CH2(5)); 69.5 (CH2Ph); 82.6 (C(2)); 85.2
(C(3)); 86.8 (C(4)); 107.5 (C(1)); 112.6 (CMe2); 128.0 (Car-p);
128.1 (Car-o); 128.5 (Car-m); 136.7 (Car-s). Anal. Calcd for
4.2.6. Benzyl 5-deoxy-2,3-O-isopropylidene-b-
(9b)
D-ribofuranoside
From mesylate 8b by reduction with LiAlH4: To a stirred solution
of 8b (10.0 g, 27.9 mmol) in dry Et2O (70 mL) under Ar, was added
at 0 °C portion wise LiAlH4 (3.0 g, 79 mmol, 3 equiv). The mixture
was stirred at rt for 3 h, then quenched portion wise with
Na2SO4ꢀ10H2O (12 g) and dropwise 10% aqueous NaOH (5 mL).
The suspension became white, Et2O (100 mL) was added. Solids
were discarded by filtration and washed with Et2O and AcOEt.
The organic phases were evaporated to give 9b as crystals which
were purified by dissolution in pentane, filtration and evaporation
(7.4 g, quant.). Sublimation (120 °C, 0.5 Torr) gave pure 9b (6.8 g,
92%).
C15H19O4Br (343.22): C, 52.49; H, 5.58; Br 23.28. Found: C, 52.8;
H, 5.8; Br, 23.9.
4.2.3. 5-Deoxy-2,3-O-isopropylidene-D-ribitol (7)
A solution of 6b (3 g, 8.7 mmol) in EtOH (30 mL) and 1 N aque-
ous KOH (30 mL) was hydrogenolysed over wet Raney-nickel
(30 g) at 50 °C for 8 h, eventually a second time. The catalyst was
then discarded and washed with EtOH, the organic solutions were
evaporated and the residue extracted with Et2O to eliminate the
inorganic salts. Evaporation of the solvent gave 7 (1.15 g, 75%).
From bromide 6b by reduction with LiAlH4: Same procedure as
above with 6b (0.47 g, 1.37 mmol), LiAlH4 (0.21 g, 5.5 mmol,
4 equiv) in dry Et2O (8 mL). The same work-up gave crude 9b
(0.22 g, 60%).
7: colourless resin, ½a D20
= ꢁ12 (c 1.0, CHCl3), Rf = 0.08 (Cyclo/
ꢂ
From bromide 6b by hydrogenolysis: A solution of 6b (0.5 g,
1.4 mmol) in EtOH (8 mL) and aqueous 1 N KOH (4.4 mmol,
4.4 mL, 3 equiv) was hydrogenolysed over Pd/C (5%) (150 mg) for
5 h at 50 °C. The catalyst was discarded by centrifugation and the
solution evaporated. The residue was dissolved in Et2O and fil-
trated through a pad of silica gel to eliminate bromide salts. Evap-
oration of the solvent gave crude 9b (0.235 g, 61%).
AcOEt 7:3). IR (KBr): 1054, 1077, 1168, 1220, 1246, 1372, 1382,
2902, 2936, 2987, 3398 cmꢁ1 1H NMR (250 MHz, CDCl3): d 1.34
.
(s, 3H, CH3); 1.36 (d, 3H, Me(5)); 1.41 (s, 3H, CH3); 3.76 (dd, 1H,
Hb-1); 3.86 (dd, 1H, Ha-1); 3.90 (dd, 1H, H-3); 3.99 (dq, 1H, H-
4); 4.30 (m, 1H, H-2); 4.85 (s, 2 OH); J(1a,1b) = 11.3, J(1a,2) = 8.4,
J(1b,2) = 4.7, J(2,3) = 5.3, J(3,4) = 8.8, J(4,Me) = 5.6 Hz. 13C NMR
(62.9 MHz, CDCl3): d 18.0 (Me(5)); 25.2 (CH3); 27.8 (CH3); 58.0
(C(1)); 65.7 (C(4)); 77.1, 81.3 (C(3), C(2)); 108.3 (CMe2). HR-MS
(ESI-Q-Tof) calcd for C8H17O4 [M+H]+: 176.1049; found: 176.1069.
9b: colourless crystals: mp 63–65 °C, lit.34
: mp 37–39 °C,
[
a
]
D = ꢁ119 (c 1.0, CHCl3), Rf = 0.58 (Cyclohexane/AcOEt 9:1). IR
(KBr): 2980, 2940, 2970, 1455, 1380, 1360, 1275, 1245, 1210,
1162, 1115, 1095, 1080, 1065, 1035, 995 865, 840, 777, 758,
700 cmꢁ1 1H NMR (250 MHz, CDCl3): d 1.31 (s, 3H, CH3); 1.35 (d,
.
4.2.4. Benzyl 2,3-O-isopropylidene-5-O-methanesulfonate-b-
ribofuranoside (8b)
D-
3H, Me(5)); 1.47 (s, 3H, CH3); 4.39 (q, 1H, H-4); 4.45 (d, 1H,
J = 11.4 Hz, CHPh); 4.54 (d, 1H, H-3); 4.72 (d, 1H, J = 11.4 Hz, CHPh);
4.74 (d, 1H, H-2); 5.14 (s, 1H, H-1); 7.33 (m, 5Har); J(1,2) = 0,
J(2,3) = 5.8, J(3,4) = 0.6, J(4,Me) = 7.0 Hz, similar values as in lit.34
13C NMR (62.9 MHz, CDCl3): d 21.1 (Me(5)); 24.9, 26.4 (CMe2);
68.7 (CH2Ph); 83.4, 85.2, 85.9 (C(2), C(3), C(4)); 107.5 (C(1));
112.1 (CMe2); 127.8 (Car-p); 128.0, 128.4 (2Car); 137.4 (Car-s).
Anal. Calcd for C15H20O4 (264.32): C, 68.16; H, 7.63. Found: C,
68.1; H, 7.6.
To a stirred solution of 5b (5.0 g, 18 mmol) in dry CH2Cl2
(40 mL) at 0 °C and NEt3 (7.0 mL, 50 mmol, ca. 3 equiv), was added
dropwise a solution of MeSO2Cl (2.1 mL, 27 mmol, 1.5 equiv) in dry
CH2Cl2 (10 mL). The solution was stirred at rt for 1 h, then washed
twice with a 20% aqueous NH4Cl and with H2O (20 mL each). The
organic phase was dried (MgSO4) and evaporated to give a resin
(7.4 g, quant.) which was crystallised in EtOH (10 mL). 8b (5.8 g,
91%) was isolated by filtration and washing with EtOH in several
crops.
8b: colourless crystals: mp 80–81 °C (EtOH), ½a D20
ꢂ
= ꢁ80 (c 1.0,
4.2.7. Benzyl 5-deoxy-2,3-O-isopropylidene-
(9
a-D-ribofuranoside
a)
CHCl3), Rf = 0.8 (Cyclohexane/AcOEt 7:3). IR (KBr): 2950, 2930,
From mesylate 8
for 9b with 8 (0.45 g, 1.24 mmol), in dry Et2O (4 mL) and LiAlH4
(0.15 g, 4 mmol, 3 equiv). The same work-up gave 9 (0.36 g,
a by reduction with LiAlH4: Same procedure as
1380, 1357, 1245, 1220, 1170, 1085, 1050, 988, 960, 820, 750,
702 cmꢁ1
.
1H NMR (250 MHz, CDCl3): d 1.32, 1.48 (2s, 2 ꢃ 3H,
a
a
CMe2); 3.02 (s, 3H, CH3SO2); 4.25 (d, 2H, CH2(5)); 4.46 (dt, 1H, H-
4); 4.49 (d, 1H, J = 11.9 Hz, CHPh); 4.70 (d, 1H, H-2); 4.71 (d, 1H,
J = 11.9 Hz, CHPh); 4.73 (dd, 1H, H-3); 5.20 (s, 1H, H-1); 7.32 (m,
5Har); J(1,2) = 0, J(2,3) = 6.1, J(3,4) = 1.0, J(4,5) = 6.7 Hz. 13C NMR
quant.) as odorous resin. The sulfurous impurities were oxidised
in CH2Cl2 (2 mL) by stirring with two drops of 30% H2O2 and some
silica gel and solid MgSO4. After evaporation of the solvent, the
residue was purified by dissolution in pentane and evaporation
(62.9 MHz, CDCl3):
d 24.8, 26.3 (CMe2); 37.7 (SO2Me); 68.5
to give 9a (0.33 g, quant.) which was used in the next step. For ana-
(CH2(5)); 69.6 (CH2Ph); 81.4 (C(2)); 84.0 (C(4)); 85.1 (C(3)); 107.5
(C(1)); 112.9 (CMe2); 128.0 (Car-p); 128.1, 128.6 (2Car); 136.7
(Car-s). Anal. Calcd for C16H22O7S (358.41): C, 53.63; H, 6.19; S,
8.92. Found: C, 53.4; H, 6.4; S, 9.2.
lytical purpose, it was purified by FC (Cyclohexane/AcOEt 9:1).
9
a
: colourless resin, ½a D20
ꢂ
= +60 (c 1.0, CHCl3), Rf = 0.5 (Cyclohex-
ane/AcOEt 9:1). IR (CHCl3): 3015, 2986, 2937, 1455, 1383, 1372,
1161, 1139, 1096, 1076, 1013, 866, 845 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): d 1.31 (d, 3H, Me(5)); 1.36, 1.56 (2s, 2 ꢃ 3H, CMe2); 4.24
(dq, 1H, H-4); 4.34 (dd, 1H, H-3); 4.60 (d, 1H, J = 12.0 Hz, CHPh);
4.71 (dd, 1H, H-2); 4.85 (d, 1H, J = 12.0 Hz, CHPh); 5.03 (d, 1H, H-
1); 7.28 (m, 1Har); 7.33 (t, J = 7.3 Hz, 2Har); 7.39 (m, 2Har);
J(1,2) = 4.4, J(2,3) = 7.2, J(3,4) = 3.8, J(4,Me) = 6.6 Hz. 13C NMR
(100 MHz, CDCl3): d 18.9 (Me(5)) 26.0, 26.1 (CMe2); 69.2 (CH2Ph);
77.4 C(4)); 81.2, 85.0 (C(2), C(3)); 100.1 C(1); 115.9 (CMe2);
127.4 (Car-p); 128.2, 127.6 (2Car); 138.0 (Car-s). Anal. Calcd for
4.2.5. Benzyl 2,3-O-isopropylidene-5-O-methanesulfonate-
ribofuranoside (8
Same reaction as for 8b, with 5
(10 mL), NEt3 (1.5 mL, 11 mmol, 3 equiv), MeSO2Cl (0.56 mL,
7 mmol, 2 equiv). After stirring for 4 h at rt, AcOEt (50 mL) was
a-D-
a)
a
(1.1 g, 3.9 mmol) in dry CH2Cl2
added and the solution worked up as above to give crude 8
a
(1.40 g, quant.) which was directly used for the next step.
8a
: colourless resin, only characterised by 1H NMR (400 MHz,
C15H20O4 (264.32): C, 68.16; H, 7.63. Found: C, 68.4; H, 7.8.
CDCl3): d 1.37, 1.56 (2s, 2 ꢃ 3H, CMe2); 3.03 (s, 3H, CH3SO2); 4.37
(s, 3H, H-4, 2 H-5); 4.63 (d, 1H, J = 12.2 Hz, CHPh); 4.65 (m, 1H,
H-3); 4.70 (dd, 1H, J = 4.2 Hz, H-2); 4.85 (d, 1H, J = 12.2 Hz, CHPh);
5.11 (d, 1H, J = 4.2, 7.0 Hz, H-1); 7.25–7.40 (m, 5Har).
4.2.8. 5-Deoxy-2,3-O-isopropylidene- -ribofuranose (10)
From anomer b: A stirred solution of 9b (0.50 g, 1.89 mmol)
in EtOH (5 mL) and formic acid (0.25 mL, 6.8 mmol) was
D

C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
1207
hydrogenolysed over 5% Pd/C (150 mg) at 30 °C for 24 h. Solid
Na2CO3 (0.36 g, 3.5 mmol) and Et2O (10 mL) were then added,
and after stirring for 20 min, the solids were discarded by centrifu-
gation. The organic solution was then evaporated to give 10
8.40 (br s, 1H, OH); J(1a,1b) = 10.9, J(1a,2) = 0, J(1b,2) = 4.9,
J(2,3) = 6.7, J(3,4) = 5.0, J(4,Me) = 6.4 Hz. 13C NMR (62.9 MHz,
CDCl3): d 11.7 (Me(5)); 24.0, 25.7 (CMe2); 62.4 (C(1)); 66.1
(C(4)); 75.4 (C(2)); 78.4 (C(3)); 110.0 (CMe2).
(0.317 g, 96%) as 90:10 to 75:25 isomeric b/
a mixture.
From anomer Same procedure with crude
a
:
9a
(0.33 g,
4.3.2. 1-Deoxy-5-hydroxyamino-3,4-O-isopropylidene-L-
1.24 mmol) in EtOH (3 mL) and formic acid (0.15 mL, 4 mmol) over
5% Pd/C (80 mg) to give crude product (0.18 g) which was purified
by FC (AcOEt/Cyclohexane 1:1) to give pure 10 (0.13 g, 59% from
erythrofuropentulose [(3R,4S)-3,4-isopropylidenedioxy-2-
methyl-1-pyrroline-N-oxide, nitrone 13]
A solution of 12 (30 mg, 0.17 mmol) was stirred at rt with HgO
(90 mg, 2.5 equiv, 0.42 mmol) for 6 h. The solids were centrifuged
off and the solvent evaporated. A separation by FC (Et2O/MeOH
9:1) gave 13 (24 mg, 80%) and 4 (6 mg, 20%).
5a).
10: colourless resin, ½a D20
= ꢁ40 (c 1.0, CHCl3), Rf = 0.21 (Cyclo/
ꢂ
AcOEt 7:3). IR (KBr): 3400, 2980, 2940, 1375, 1230, 1160, 1110,
1070, 1000, 865 cmꢁ1
.
1H NMR (250 MHz, CDCl3) major anomer
13, colourless crystals: mp 112–114 °C, ½a D20
ꢂ
= +5 (c 1.0, CHCl3),
b: d 1.32 (s, 3H, CH3); 1.36 (d, 3H, Me(5)); 1.48 (s, 3H, CH3); 2.81
(d, 1H, OH-1); 4.37 (dq, 1H, H-4); 4.57 (dd, 1H, H-3); 4.68 (d, 1H,
H-2); 5.43 (br s, 1H, H-1); J(1,2) = ca. 0, J(1,OH) = 1.8, J(2,3) = 6.1,
J(3,4) = 1.2, J(4,Me) = 7.0 Hz, similar values as in lit. 35,36; minor
Rf = 0.23 (Et2O/MeOH 9:1). 1H NMR (250 MHz, CDCl3): d 1.40 (s, 6H,
2 Me); 2.10 (dd, 3H, Me(1)); 4.10 (dhex, 1H, Hb-5); 4.13 (dm, 1H,
Ha-5); 4.82 (ddd, 1H, H-4); 5.16 (m, 1H, H-3); J(3,4) = 6.2,
J(3,Me) = 1.5, J(3,5a) = 0.8, J(3,5b) = 1.2, J(4,5a) = 4.8, J(4,5b) = 1.6,
J(5a,5b) = 14.8, J(5a,Me) = 2.2, J(5b,Me) = 1.5 Hz. 13C NMR
(62.9 MHz, CDCl3): d 10.5 (Me(1)); 25.8, 27.1 (CMe2); 67.1 (C(5));
71.6 (C(4)); 82.3 (C(3)); 102.5 (C(2)); 112.1 (CMe2). HR-MS (Tof-
ES+) calcd for C8H14O3N [M+H]+: 172.0974; found 172.0910.
anomer
a
: d 1.23 (d, Me(5)); 1.39, 1.57 (2s, 2 ꢃ 3H, CMe2); 3.91
(d, 1H, OH-1); 4.19 (qd, 1H, H-4); 4.42 (dd, 1H, H-3); 4.67 (dd,
1H, H-2); 5.28 (dd, 1H, H-1); J(1,OH) = 9.3, J(1,2) = 4.2, J(2,3) = 6.7,
J(3,4) = 3.0, J(4,Me) = 6.7 Hz. 13C NMR (62.9 MHz, CDCl3) major ano-
mer b: d 21.6 (Me(5)); 24.9, 26.4 (CMe2); 83.2, 85.4, 86.3 (C(2), C(3),
(C(4)); 103.2 (C(1)); 112.2 (CMe2), similar values as in lit.36; minor
4.3.3. 5-Deoxy-2,3-O-isopropylidene-D-ribose, oxime (14)
anomer
a
: d 18.3 (Me(5)); 24.9, 26.2 (CMe2); 76.4, 79.5, 84.8 (C(2),
A solution of 12 (0.61 g, 3.5 mmol) in EtOH (4 mL) and H2O
(4 mL), was stirred at 50 °C under Ar with NaHCO3 (0.44 g,
5.3 mmol, 1.5 equiv) and NH2OHꢀHCl (365 mg, 5.3 mmol,
1.5 equiv) for 4 h. The solution was then extracted thrice with
AcOEt, the organic phase dried (MgSO4) and evaporated to give
oxime 14 (0.64 g, 96%) as 60:40 E/Z mixture.
C(3), C(4)); 95.4 (C(1)); 115.0 (CMe2). Anal. Calcd for C8H14O4
(174.20): C, 55.16; H, 8.10. Found: C, 55.2; H, 8.2.
4.2.9. 5-Deoxy-2,3-O-isopropylidene-1,4-Di-O-methanesulfonyl-
D
-ribitol (11)
To a solution of 7 (1.5 g, 8.5 mmol) in dry CH2Cl2 (15 mL) at 0 °C
14: colourless resin, ½a D20
ꢂ
= +2 (c 1.0, CHCl3), Rf = 0.17 (E), 0.13
(Z) (Cyclo/AcOEt 7:3). IR (CHCl3): 3340, 2990, 1650, 1385, 1376,
was added NEt3 (3.6 mL, 26 mmol, 3 equiv) and dropwise MeSO2Cl
(2.0 mL, 26 mmol, 3 equiv). The solution was stirred for 2 h at rt,
then diluted with CH2Cl2 (50 mL) and washed twice with aqueous
NaHCO3 solution and then with H2O, dried (MgSO4) and evapo-
rated. The crude product was purified by FC (Cyclohexane/AcOEt
6:4) to give 11 (900 mg, 30%). It was used without further purifica-
tion and was characterised by NMR only.
1240, 1220, 1160, 1070 cmꢁ1 1H NMR (250 MHz, CDCl3): minor
.
isomer Z: d 1.26 (d, 3H, Me(5)); 1.39, 1.52 (2s, 2 ꢃ 3H, CMe2);
3.79 (quint, 1H, H-4); 4.14 (dd, 1H, H-3); 5.35 (dd, 1H, H-2); 6.92
(d, 1H, H-1); 8.40 (br s, 1H, OH); J(1,2) = 5.8, J(2,3) = 6.4,
J(3,4) = 7.6, J(4,Me) = 6.4 Hz; major isomer E:
d 1.30 (d, 3H,
Me(1)); 1.39, 1.49 (2s, 2 ꢃ 3H, CMe2); 3.90 (dq, 1H, H-4); 4.04
(dd, 1H, H-3); 4.77 (dd, 1H, H-2); 7.52 (d, 1H, H-1); 9.8 (br s,
OH); J(1,2) = 7.3, J(2,3) = 6.0, J(3,4) = 7.6, J(4,Me) = 6.1 Hz. 13C NMR
(62.9 MHz, CDCl3) minor isomer Z: d 19.6 (Me(5)); 25.2, 27.4
(CMe2); 67.0 (C(4)); 71.5 (C(2)); 82.5 (C(3)); 109.8 (CMe2); 152.4
(C(1)); major isomer E: d 20.0 (Me(5)); 25.3, 27.6 (CMe2); 66.0
(C(4)); 75.0 (C(2)); 82.0 (C(3)); 109.9 (CMe2); 150.2 (C(1)). Anal.
Calcd for C8H15O4N (189.21): C, 50.78; H, 7.99; N, 7.40. Found: C,
51.0; H, 8.1; N, 7.1.
11: yellowish resin, ½a D20
= ꢁ17 (c 1.0, CHCl3), Rf = 0.22 (Cyclo-
ꢂ
hexane/AcOEt 6:4). 1H NMR (250 MHz, CDCl3): d 1.38, 1.49 (2s,
2 ꢃ 3H, CMe2); 1.59 (d, 3H, Me(5)); 3.09 (2s, 6H, 2 CH3SO2); 4.15
(dd, 1H, J = 5.8, 7.3 Hz, H-3); 4.31 (m, 1 H); 4.48 (m, 2H,); 4.90
(dq, 1H, J = 7.3, 6.4 Hz, H-4); 1H NMR (250 MHz, C6D6): 1.08, 1.24
(2s, 2 ꢃ 3H, CMe2); 1.25 (d, 3H, Me(5)); 2.31, 2.33 (2s, 2 ꢃ 3H, 2
CH3SO2); 3.63 (dd, 1H, H-3); 4.06 (m, 1H, H-2); 4.20 (dd, 1H, Hb-
1); 4.36 (dd, 1H, Ha-1); 4.70 (dq, 1H, H-4); J(1a,1b) = 10.8,
J(1a,2) = 3.8, J(1b,2) = 7.0, J(2,3) = 5.8, J(3,4) = 7.8, J(4,Me) = 6.4 Hz.
13C NMR (62.9 MHz, CDCl3): d 18.2 (Me(5)); 25.1 (CH3); 27.3
(CMe2); 37.3 (CH3SO2); 39.1 (CH3SO2); 68.0 (C(1)); 74.6, 75.4,
77.5 (C(2), C(3), (C(4)); 109.4 (CMe2).
4.3.4. 5-Deoxy-2,3-O-isopropylidene-D-ribose, O-
(tertiobutyldimethyl)silyl-oxime (15)
A solution of 14 (0.52 g, 2.75 mmol) and ClSiMe2tBu (0.83 g,
5.5 mmol, 2 equiv) in dry pyridine (5 mL) under Ar was stirred at
rt for 16 h. The solvent was evaporated, the residue dissolved in
Et2O and the organic solution washed twice with brine and with
H2O, dried (MgSO4) and evaporated. Purification by FC (Cyclohex-
ane/AcOEt 7:3) gave 15 (0.56 g, 67%).
4.3. Amino-L-lyxose derivatives
4.3.1. 1,4,5-Trideoxy-N-hydroxy-1,4-imino-2,3-O-isopropylidene-
L-lyxitol (12)
15: colourless resin, ½a D20
ꢂ
= +25 (c 1.0, CHCl3), Rf = 0.60 (E), 0.66
(Z) (Cyclohexane/AcOEt 7:3). IR (KBr): 786, 838, 936, 1066, 1205,
To a solution of 11 (360 mg, 1.08 mmol) in NEt3 (3.5 mL) was
added NH2OHꢀHCl (301 mg, 4.34 mol, 4 equiv) and DBU (30
l
L,
1219, 1252, 1373, 1382, 1463, 1473, 2850, 2932, 2958,
0.22 mmol, 0.2 equiv), and this suspension stirred at 85 °C for 6–
7 h. NEt3 was evaporated and the white solid extracted with
Et2O. The solvent was evaporated and the residue purified par FC
(CH2Cl2/Ether 95:5) to give 12 (84 mg, 45%). This product was
rather oxidisable and characterised by NMR only.
3492 cmꢁ1 1H NMR (250 MHz, CDCl3) minor isomer Z: d 0.19,
.
0.20 (2s, 2 ꢃ 3H, SiMe2); 0.94 (s, 9H, SitBu); 1.25 (d, 3H, Me(5));
1.39, 1.51 (2s, 2 ꢃ 3H, CMe2); 3.12 (s, 1H, OH); 3.71 (dq, 1H, H-
4); 4.09 (dd, 1H, H-3); 5.34 (t, 1H, H-2); 7.04 (d, 1H, H-1);
J(1,2) = 5.8, J(2,3) = 6.4, J(3,4) = 7.9, J(4,Me) = 6.1 Hz; major isomer
E: d 0.16, 0.17 (2s, 2 ꢃ 3H, SiMe2); 0.93 (s, 9H, tBuSi); 1.29 (d, 3H,
Me(5)); 1.38, 1.48 (2s, 2 ꢃ 3H, CMe2); 2.48 (s, 1H, OH); 3.87 (dq,
1H, H-4); 4.03 (dd, 1H, H-3); 4.79 (t, 1H, H-2); 7.59 (d, 1H, H-1);
J(1,2) = 7.3, J(2,3) = 6.1, J(3,4) = 7.6, J(4,Me) = 6.1 Hz. 13C NMR
12: colourless resin, [a]D = +47 (c 1.0, CHCl3), Rf = 0.1 (CH2Cl2/
Ether 95:5). 1H NMR (250 MHz, CDCl3): d 1.28 (s, 3H, CH3); 1.31
(d, 3H, Me(5)); 1.42 (s, 3H, CH3); 2.59 (dq, 1H, H-4); 2.67 (dd, 1H,
H-1b); 3.45 (d, 1H, H-1a); 4.49 (dd, 1H, H-3); 4.61 (dd, 1H, H-2);

1208
C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
(62.9 MHz, CDCl3) minor isomer Z: d ꢁ5.4 (Me2Si); 18.1 (SiCMe3);
19.7 (Me(5)); 25.4 (Me); 25.9 (SiCMe3); 27.6 (Me); 66.0 (C(4));
75.2 (C(2)); 83.0 (C(3)); 109.9 (CMe2); 156.3 (C(1)); major isomer
E: d ꢁ5.3 (Me2Si); 18.0 (SiCMe3); 19.7 (Me(5)); 25.3 (Me); 25.9
(SiCMe3); 27.5 (Me); 67.0 (C(4)); 72.2 (C(2)); 82.4 (C(3)); 109.8
(CMe2); 154.4 (C(1)). HR-MS (Q-Tof) calcd for C14H19O4NSi [M]+:
303.1866; found: 303.1881.
(s, 3H, Me); 1.45 (d, 3H, Me-6); 1.46 (s, 3H, Me); 3.98 (dq, 1H, H-
6); 4.27 (dt, 1H, H-5); 4.45 (dd, 1H, H-4); 7.28 (t, 1H, H-3);
J(3,4) = 2.1, J(3,5) = 1.6, J(4,5) = 6.6, J(5,6) = 1.2, J(6,Me) = 6.6 Hz.
13C NMR (62.9 MHz, CDCl3): d 16.2 (Me-6); 26.5, 27.3 (CMe2);
65.4 (C(6)); 71.4 (C(4)); 72.8 (C(5)); 112.2 (CMe2); 147.9 (C(3)).
Anal. Calcd for C8H15O3N (171.19): C, 56.12; H, 7.65; N, 8.18.
Found: C, 56.0; H, 7.8; N, 7.9.
18: colourless resin, Rf = 0.4 (AcOEt/CHCl3/MeOH 80:15:5). 1H
NMR (250 MHz, CDCl3): d 1.27 (d, 3H, Me(5)); 1.40, 1.59 (2s,
2 ꢃ 3H, CMe2); 2.49 (br s, 1H, OH); 4.09 (dq, 1H, H-4); 4.28 (dd,
1H, H-3); 4.53 (d, 1H, H-2); 6.23, 6.59 (2br s, 2H, NH2);
J(2,3) = 8.0, J(3,4) = 2.9, J(4,Me) = 5.0 Hz. 13C NMR (62.9 MHz,
CDCl3): d 20.2 (Me(5)); 24.2, 26.6 (CMe2); 65.0 (C(4)); 75.8 (C(2));
80.8 (C(3)); 109.4 (CMe2); 173.2 (C(1)). HR-MS (FAB+) calcd for
C8H16O4N [M+H]+: 190.1079; found: 190.1084.
4.3.5. 5-Deoxy-2,3-O-isopropylidene-4-O-methanesulfonyl-
D-
ribose, O-(tertiobutyl-dimethyl)silyl-oxime (16)
To a solution of 15 (0.50 g 1.35 mmol) at 0 °C in dry CH2Cl2
(5 mL) were added NEt3 (0.46 mL, 3.3 mmol, 2 equiv) and dropwise
ClSO2Me (0.192 mL, 2.5 mmol, 1.5 equiv). After stirring at rt for 6 h
(tlc monitoring in CH2Cl2), the solution was diluted with CH2Cl2
(40 mL), washed twice with 20% aqueous NH4Cl then with H2O,
dried (MgSO4) and evaporated. Purification by FC (Cyclohexane/
AcOEt 7:3) gave 16 (0.63 g, quant.) unstable and directly used in
the following step.
21: colourless resin, Rf = 0.74 (CH2Cl2/MeOH 95:5). 1H NMR
(250 MHz, CDCl3): d 1.41, 1.58 (2s, 2 ꢃ 3H, CMe2); 1.67 (d, 3H,
Me(5)); 3.11 (s, 3H, MeSO2); 4.19 (dd, 1H, H-3); 4.93 (d, 1H, H-
2); 5.00 (dq, 1H, H-4); J(2,3) = 5.4, J(3,4) = 7.7, J(4,Me) = 6.2 Hz.
13C NMR (62.9 MHz, CDCl3): d 18.9 (Me); 25.8, 26.8 (CMe2); 39.0
(MeSO2); 66.6 (C(2)); 76.9 (C(4)); 78.8 (C(3)); 113.3 (CMe2);
116.3 (CN). HR-MS (FAB+) calcd for C9H16O5NS [M+H]+: 250.0749;
found 250.0758.
16: colourless resin, ½a D20
ꢂ
= +42 (c 1.0, CHCl3), Rf = 0.55 (Cyclo-
hexane/AcOEt 7:3). 1H NMR (250 MHz, CDCl3) minor isomer Z: d
0.15, 0.21 (2s, 2 ꢃ 3H, Me2Si); 0.95 (s, 9H, tBuSi); 1.36 (d, 3H,
Me(5)); 1.40, 1.55 (2s, 2 ꢃ 3H, CMe2); 3.00 (s, 3H, MeSO2); 4.62
(dd, 1H, H-3); 4.76 (dq, 1H, H-4); 5.29 (dd, 1H, H-2); 7.10 (d, 1H,
H-1); J(1,2) = 4.1, J(2,3) = 7.7, J(3,4) = 2.7, J(4,Me) = 6.4 Hz; major
isomer E: d 0.17, 0.21 (2s, 2 ꢃ 3H, Me2Si); 0.93 (s, 9H, tBuSi); 1.40,
1.50 (2s, 2 ꢃ 3H, CMe2); 1.51 (d, 3H, Me(5)); 3.02 (s, 3H, MeSO2);
4.24 (t, 1H, H-3); 4.81 (dd, 1H, H-2); 4.89 (dq, 1H, H-4); 7.53 (d,
1H, H-1); J(1,2) = 8.4, J(2,3) = 6.5, J(3,4) = 6.4, J(4,Me) = 6.4 Hz. 13C
NMR (62.9 MHz, CDCl3) minor isomer Z: d ꢁ5.3 (2 CH3Si); 16.8
(SiCMe3); 18.0 (Me(5)); 24.3 (Me); 26.0 (tBuSi); 26.1 (Me); 38.9
(MeSO2); 71.7 (C(4)); 77.2 (C(2)); 79.0 (C(3)); 110.0 (CMe2);
152.8 (C(1)); major isomer E: d ꢁ5.2 (2MeSi); 16.8 (SiCMe3); 18.1
(Me(5)); 25.1 (Me); 25.9 (tBuSi); 27.4 (Me); 39.0 (MeSO2); 74.7
(C(4)); 75.7 (C(2)); 78.9 (C(3)); 109.6 (CMe2); 151.4 (C(1)).
4.3.7. 4-Amino-1,4,5-trideoxy-L-lyxofuranose-1-sulfonic acid
(20)
A solution of 4 (50 mg, 0.3 mmol) in H2O (0.5 mL) was stirred
under SO2 atmosphere at rt for 24 h. EtOH (2 mL) was then added
and the solution was left at 0 °C for 15 h. The crystals were isolated
by centrifugation and washing with MeOH to give 20 (43 mg, 75%)
in two crops.
20: colourless crystals: mp 210–215 °C (dec), (lit.13 210 °C
(dec)), ½a 2D0
= ꢁ11 (c 1.0, H2O). IR (KBr): 518, 572, 622, 835, 991,
ꢂ
1010, 1046, 1205, 1316, 1408, 1576, 1634, 3020, 3450 cmꢁ1 1H
.
NMR (400 MHz, D2O) and 13C NMR (100 MHz, D2O): same values
as in lit.13 Anal. Calcd for C5H11O5NS (197.21): C, 30.45; H, 5.62;
N, 7.10; S, 16.26. Found: C, 29.8; H, 5.3; N, 6.8; S, 16.1.
4.3.6. 4,5-Dideoxy-4-(hydroxylamino)-2,3-O-isopropylidene-L-
lyxofuranose [(3S,4R,5S)-2,3-isopropylidenedioxy-4-methyl-1-
pyrroline-N-oxide, nitrone 4], (3S,4S,5S)-5,6-
isopropylidenedioxy-6-methyl 5,6-dihydro-4H-(1,2)oxazine
(17), 5-deoxy-2,3-O-isopropylidene-4-O-methanesulfonyl-D-
4.3.8. 4,5-Dideoxy-4-(hydroxylamino)-L-lyxofuranose
[(3S,4R,5S)-4-Methyl-1-oxy-1-pyrroline-3,4-diol, nitrone 21]
A solution of 4 (50 mg, 0.3 mmol) in MeOH (0.4 mL) and 6 N
aqueous HCl (0.25 mL) was stirred at rt for 9 h. Solid NaHCO3
(0.26 g, 3 mmol) and MeOH (0.5 mL) were added and the mixture
was stirred for another 2 h, the solids were centrifuged off and
washed thrice with MeOH and the solvents evaporated. The ob-
tained crystals were washed with CH2Cl2 to give pure 21 (38 mg,
99%).
ribononitrile (18) and 5-deoxy-2,3-O-isopropylidene-D-
ribonamide (19)
A
solution of 16 (2.0 g, 5.25 mmol) with crystallised
NBu4Fꢀ3H2O (2.75 g, 8.7 mmol, 1.7 equiv) and NEt3 (1.1 mL
7.9 mmol, 1.5 equiv) in MeCN (20 mL) was stirred at 80 °C for
6 h. The solvent was evaporated and the residue dissolved in
CH2Cl2 (50 mL), washed thrice with 20% aqueous NH4Cl solution.
The aqueous solutions were extracted several times with CH2Cl2,
the combined organic phases dried (MgSO4) and evaporated. Puri-
fication by FC (AcOEt/CHCl3/MeOH 8:1.5:0.5) gave 4 (0.40 g, 45%),
then 17 (0.19 g, 21%), 18 (1%) and 19 (1%). The same procedure
with NBu4Fꢀ3H2O (1.3 equiv) gave 4 (60%) and 17 (6%).
21: colourless crystals: mp 148–152 °C (dec). 1H NMR
(400 MHz, D2O): d 1.41 (d, 3H, Me(5)); 4.27 (quint, 1H, H-4); 4.60
(t, 1H, H-3); 5.01 (d, 1H, H-2); 7.31 (s, 1H, H-1); J(2,3) = 4.9,
J(2,4) = 1.0, J(3,4) = 5.5, J(4,Me) = 6.9 Hz. 13C NMR (100 MHz,
D2O): d 10.4 (Me(5)); 69.2 (C(2)); 70.3 (C(4)); 71.0 (C(3)); 140.8
(C(1)). HR-MS (FAB+) calcd for C5H10O3N [M+H]+: 132.0675; found:
132.0661.
4: colourless crystals: mp 92–94 °C, ½a D20
= ꢁ3 (c 1.0, CHCl3),
ꢂ
Rf = 0.32 (Et2O/MeOH 9:1). IR (KBr): 515, 683, 878, 1006, 1050,
1119, 1148, 1168, 1210, 1260, 1383, 1578, 2945, 2983, 2995,
3464 cmꢁ1
.
1H NMR (250 MHz, CDCl3): d 1.40, 1.45 (2s, 2 ꢃ 3H,
4.3.9. (4S,5S,6S)-6-Methyl-5,6-dihydro-4H-(1,2)oxazine-4,5-diol
(22)
CMe2); 1.51 (d, 3H, Me(5)); 4.10 (ddq, 1H, H-4); 4.88 (t, 1H, H-3);
5.27 (ddd, 1H, H-2); 6.92 (t, 1H, H-1); J(1,2) = 1.8; J(1,4) = 2.1;
J(2,3) = 6.4; J(2,4) = 0.8; J(3,4) = 5.4; J(4,Me) = 7.1 Hz. 13C NMR
(62.9 MHz, CDCl3): d 11.0 (Me(5)); 25.8, 27.0 (CMe2); 71.1 (C(4));
75.8 (C(2)); 77.8 (C(3)); 112.0 (CMe2); 131.5 (C(1)). HR-MS (FAB+)
calcd for C8H16O3N [M+H]+: 172.0974; found: 172.0973.
A solution of 17 (40 mg, 0.23 mmol) in MeOH (0.3 mL) was stir-
red at rt with 6 N HCl (0.1 mL) for 5 h. The solvent was evaporated
to give 22 (25 mg, 81%), rather unstable, characterised by NMR
only.
24: colourless resin, Rf = 0.08 (Cyclohexane/AcOEt 5:5). 1H NMR
(250 MHz, D2O): d 1.30 (d, 3H, Me-6); 3.91 (dd, 1H, H-4); 4.16 (q,
1H, H-6); 4.41 (dt, 1H, H-5); 7.21 (dd, 1H, H-3); J(3,5) = 1.2,
J(3,4) = 2.2, J(4,5) = 4.8, J(4,6) = ca. 0.8, J(5,6) = 1.2, J(6,Me) = 6.6 Hz.
17: colourless crystals: mp 104–106 °C, ½a D20
= ꢁ54 (c 1.0,
ꢂ
CHCl3), Rf = 0.28 (Et2O/MeOH 9:1), IR (KBr): 508, 792, 863, 914,
1010, 1042, 1090, 1143, 1187, 1225, 1264, 1373, 1450, 1775,
1789, 2941, 2965, 2995 cmꢁ1 1H NMR (250 MHz, CDCl3): d 1.41
.

C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
1209
13C NMR (62.9 MHz, D2O): d 15.5 (Me-6); 63.5 (C(4)); 64.6 (C(6));
75.2 (C(5)); 151.6 (C(3)).
(Car-s). HR-MS (Tof, ES+).: 252 (100%), 190 (12), 176 (33). Anal.
Calcd for C16H21O4N (291.34): C, 65.95; H, 7.27; N, 4.81. Found:
C, 65.4; H, 7.1; N, 4.7.
4.3.10. (4S,5S,6S)-4,5-Isopropylidenedioxy-6-methyl-
(1,2)oxazinane (23) and (4S,5S,6S)-6-methyl-(1,2)oxazinane-4,5-
diol (24)
4.4.3. (2S,3aS,4S,5R,6S)-2-Ethyloxy-4,5-isopropylidenedioxy-6-
methyl-hexahydro-pyrrolo[1,2-b]isoxazole (26a)
A solution of 17 (36 mg, 0.21 mmol) in AcOH (0.4 mL) was stir-
red at rt under Ar with NaBH3CN (16 mg, 0.26 mmol, 1.25 equiv)
for 5 h. MeOH (5 mL) was then added and the solvents evaporated.
The residue was purified by FC (Cyclohexane/AcOEt 7:3) to give 23
(16 mg, 44%).
A solution of 23 (16 mg, 0.09 mmol) in MeOH (0.12 mL) was
stirred at rt with 6 N HCl (40 lL) for 7 h. Solid NaHCO3 was added
and was stirred for another 1 h, the solids were filtered out and
washed with MeOH and the solvents evaporated to give pure 24
(12 mg, quant.).
Same procedure as for 26b with 4 (0.10 g, 0.58 mmol) and 25a
(0.28 mL, 2.9 mmol, 5 equiv) to give 26a (0.14 g, quant.).
26a: colourless crystals: mp 88–90 °C, ½a D20
ꢂ
= +147 (c 1.0, CHCl3),
Rf = 0.82 (Ether/MeOH 9:1). IR (KBr): 514, 645, 855, 878, 1002, 1041,
1091, 1207, 1240, 1372, 1449, 2946, 2978 cmꢁ1. 1H NMR (400 MHz,
CDCl3): d 1.18 (t, 3H, CH2CH3); 1.31 (d, 3H, Me-6); 1.32, 1.51 (2s,
2 ꢃ 3H, CMe2); 2.03 (ddd, 1H, Hb-3); 2.29 (dd, 1H, Ha-3); 3.07 (dq,
1H, H-6); 3.40 (dq, 1H, CHbCH3); 3.81 (dq, 1H, CHaCH3); 3.96 (dd,
1H, H-3a); 4.62 (d, 1H, H-4); 4.68 (t, 1H, H-5); 5.25 (d, 1H, H-2);
J(2,3a) = 0, J(2,3b) = 5.2, J(3a,3b) = 12.7, J(3a,H-3a) = 7.0, J(3b,H-
3a) = 11.0, J(H-3a,4) = 0, J(4,5) = 6.5, J(5,6) = 5.0, J(6,Me-6) = 7.0,
J(CHa,CHb(Et)) = 9.3, J(CHa,CH3) = J(CHb,CH3) = 7.1 Hz; 13C NMR
(100 MHz, CDCl3): d 13.4 (Me-6); 14.8 (CH2CH3); 25.0, 26.0 (CMe2);
38.3 (C(3)); 62.8 (CH2CH3); 65.9 (C(6)); 68.6 (C(3a)); 80.8 (C(4));
81.6 (C(5)); 103.0 (C(2)); 11.6 (CMe2). Anal. Calcd for C12H21NO4
(243.31): C, 59.24; H, 8.70; N, 5.76. Found: C, 58.8; H, 8.5; N, 5.6.
23: colourless resin, characterised by NMR only. 1H NMR
(400 MHz, CDCl3): d 1.32 (d, 3H, Me-6); 1.36, 1.53 (2s, 2 ꢃ 3H,
CMe2); 3.06 (dd, 1H, Hb-3); 3.13 (dd, 1H, Ha-3); 3.97 (dd, 1H, H-
5); 4.08 (s, 1H, H-6); 4.28 (ddd, 1H, H-4); 5.50 (s, 1H, NH);
J(3a,3b) = 12.4, J(3a,4) = 6.9, J(3b,4) = 9.8, J(4,5) = 5.1, J(5,6) = 2.2,
J(6,Me) = 6.7 Hz. 13C NMR (62.9 MHz, CDCl3): d 15.7 (Me); 26.4,
28.3 (CMe2); 51.0 (C(3)); 70.8 (C(4)); 74.3 (C(5)); 74.6 (C(6));
109.2 (CMe2).
4.4.4. Ethyl (2S,3S,4R,5S)-1-benzyl-3,4-isopropylidenedioxy-5-
methyl-pyrrolidine-2-acetate (27a)
A solution of 26a (100 mg, 0.4 mmol) in tetrachlorethane (1 mL)
and BnBr (50 lL, 0.4 mmol, 1.2 equiv) was stirred for 24 h at 50 °C.
24: colourless resin. 1H NMR (250 MHz, D2O): d 1.19 (d, 3H, Me-
6); 2.98 (dd, 1H, H-3b); 3.11 (dd, 1H, H-3a); 3.77 (dt, 1H, H-5); 3.88
(ddd, 1H, H-4); 3.89 (dq, 1H, H-6; J(3a,3b) = 13.0; J(3a,4) = 11.2,
J(3b,4) = 5.2, J(3b,5) = 1.0, J(4,5) = 3.2, J(5,6) = 1.0, J(6,Me) = 6.5 Hz.
13C NMR (62.9 MHz, D2O): d 18.0 (Me-6); 50.3 (C(3)); 69.7 (C(4));
72.2 (C(6)); 81.3 (C(5)). HR-MS (FAB+) calcd for C5H12O3N
[M+H]+: 134.0817; found: 134.0810.
After dilution with AcOEt, the solution was washed with 1 N aque-
ous NaHCO3, dried (MgSO4) and evaporated. Purification by FC
(Cyclohexane/AcOEt 8:2) gave 27a (48 mg, 35%)
27a: yellowish resin, ½a D20
ꢂ
= +54 (c 1.0, CHCl3), Rf = 0.7 (Cyclo-
hexane/AcOEt 7:3). IR (KBr): 699, 746, 873, 1003, 1029, 1072,
1111, 1128, 1162, 1180, 1210, 1244, 1371, 1474, 1731, 2810,
4.4. Cycloaddition adducts and derivatives
2935, 2984 cmꢁ1 1H NMR (400 MHz, CDCl3, 330 K): d 1.12 (d,
.
4.4.1. Phenoxyethylene (25b)
3H, Me-5); 1.18 (t, 3H, J = 7.1 Hz, CH2CH3); 1.33, 1.56 (2s, 2 ꢃ 3H,
CMe2); 2.16 (dd, 1H, Hb-20); 2.48 (dd, 1H, Ha-20); 2.89 (dq, 1H, H-
5); 3.49 (dd, 1H, H-2); 3.50, 3.90 (2d, 2 ꢃ 1H, J = 14.3 Hz, CH2Ph);
4.06 (m, 2H, CH2CH3); 4.52 (d, 1H, H-3); 4.56 (dd, 1H, H-4); 7.22
(t, 1Har-p); 7.29 (t, 2Har-m); 7.35 (d, 2Har-o); J(20a,20b) = 14.5,
J(20a,2) = 4.2, J(20b,2) = 9.7, J(2,3) = 0.8, J(3,4) = 6.4, J(4,5) = 4.7,
J(5,Me) = 6.3, J(Ho,Hm) = J(Hm,Hp) = 7.3 Hz. 13C NMR (100 MHz,
CDCl3): d 12.7 (Me-5); 14.0 (CH2CH3); 25.4, 26.4 (CMe2); 30.4
(C(20)); 50.4 (CH2Ph); 58.7 (C(5)); 60.5 (CH2CH3); 62.2 (C(2)); 81.5
(C(4)); 82.9 (C(3)); 111.6 (CMe2); 126.8 (Car-p); 128.1, 128.3
(2Car); 137.7 (Car-s); 172.0 (CO2). Anal. Calcd for C19H27O4N +
0.25 H2O (337.92): C, 67.53; H, 8.20; N, 4.14. Found: C, 67.2; H,
8.0; N, 3.9.
Same procedure as in lit.32 with modifications: a biphasic solu-
tion of 2-bromo-1-phenoxy éthane32b (20.0 g, 0.1 mol), NBu4HSO4
(33 g, 0.1 mol) in Et2O (400 mL) and 50% aqueous NaOH (100 mL)
was vigorously stirred at rt for 4 h. The organic phase was washed
with H2O (3 ꢃ 50 mL), the aqueous phases were extracted with
Et2O (2 ꢃ 50 mL), the combined organic phases dried (MgSO4)
and evaporated. 27b was purified by distillation (7.8 g, 65%) at
70 °C, 28 Torr. The reaction in toluene as in lit.32b gave a weaker
yield (40%).
1H NMR (250 MHz, CDCl3): similar values as in lit.37
4.4.2. (2S,3aS,4S,5R,6S)-4,5-Isopropylidenedioxy-6-methyl-2-
phenoxy-hexahydro-pyrrolo[1,2-b]isoxazole (26b)
A
solution of
4
(0.25 g, 1.46 mmol) in tetrachlorethane
4.4.5. Phenyl (2S,3S,4R,5S)-1-benzyl-5-methyl-3,4-
isopropylidenedioxy-pyrrolidine-2-acetate (27b)
Same procedure as for 27a with 26b (50 mg, 0.17 mmol) and
BnBr (20 lL, 0.17 mmol, 1 equiv) in tetrachlorethane (0.5 mL) at
100 °C, to give 27b (44 mg. 67%) after purification by FC (Cyclohex-
(0.12 mL) was stirred with 25b (0.35 g, 2.92 mmol, 2 equiv) at
50 °C for 16 h. The solvent was evaporated and the residue crystal-
lised in iPr2O and washed with Cyclohexane to give 26b (0.36 g,
85%). Rather unstable compound.
26b: colourless crystals: mp 110–112 °C, ½a D20
ꢂ
= +219 (c 1.0,
ane/AcOEt 7:3).
CHCl3), Rf = 0.8 (Ether/MeOH 9:1). IR (KBr): 692, 757, 860, 888,
27b: yellowish resin, ½a D20
ꢂ
= +37 (c 1.0, CHCl3), Rf = 0.54 (Cyclo-
hexane/AcOEt 7:3). IR (KBr): 690, 738, 871, 910, 934, 1002, 1026,
933, 969, 1002, 1047, 1075, 1085, 1136, 1190, 1209, 1226, 1372,
1497, 1588, 1601, 2933, 2987 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d
1070, 1196, 1379, 1493, 1593, 1754, 2804, 2935, 2986 cmꢁ1 1H
.
1.33 (d, 3H, Me-6); 1.52, 1.56 (2s, 2 ꢃ 3H, CMe2); 2.27 (ddd, 1H,
Hb-3); 2.60 (dd, 1H, Ha-3); 3.18 (m, 1H, H-6); 4.11 (dd, 1H, H-
3a); 4.69 (dd, 1H, H-4); 4.75 (dd, 1H, H-5); 5.90 (d, 1H, H-2);
6.98 (m, 3Har); 7.26 (m, 2Har-m); J(2,3a) = 0, J(2,3b) = 5.2, J(3a,H-
3a) = 6.9, J(3b,H-3a) = 10.5, J(3a,3b) = 13.0, J(3a,4) = 1.2, J(H-
3a,4) = 0, J(4,5) = 6.4, J(5,6) = 5.1, J(6,Me-6) = 6.5 Hz. 13C NMR
(100 MHz, CDCl3): d 13.4 (Me-6); 25.1, 26.0 (CMe2); 38.6 (C(3));
66.0 (C(6)); 68.5 (C(3a)); 81.0 (C(4)); 81.7 (C(5)); 101.5 (C(2));
112.0 (CMe2); 116.6 (Car-o); 121.9 (Car-m); 129.3 (Car-p); 156.6
NMR (400 MHz, CDCl3): d 1.16 (d, 3H, Me-5); 1.34, 1.58 (2d,
2 ꢃ 3H, CMe2); 2.42 (dd, 1H, Ha-20); 2.75 (dd 1H, Hb-20); 2.99 (m,
1H, H-5); 3.59 (d, 1H, J = 14.0 Hz, CHPh); 3.62 (m, 1H, H-2); 3.98
(d, 1H, J = 14.0 Hz, CHPh); 4.62 (dt, 1H, H-4); 4.65 (d, 1H, H-3);
7.00 (d, J = 7.3 Hz, 2Har-o); 7.20–7.40 (m, 8Har); J(2,3) = 0.6,
J(3,4) = 6.4, J(4,5) = 4.6, J(5,Me) = 6.4, J(20a,2) = 4.2, J(20b,2) = 9.6,
J(20a,20b) = 14.5 Hz. 13C NMR (100 MHz, CDCl3): d 12.6 (Me-5);
25.4, 26.4 (CMe2); 30.9 (C(20)); 50.4 (CH2Ph); 58.7 (C(5)); 62.4
(C(2)); 81.5 (C(4)); 82.9 (C(3)); 111.8 (CMe2); 121.5 (C-o(OPh));

1210
C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
125.8 (C-p(OPh)); 126.9 (C-p(Bn)); 128.1 (C-o(Bn)); 128.8 (C-
m(Bn)); 129.4 (C-m(OPh)); 139.1 (C-s(Bn)); 150.5 (C-s(OPh));
170.6 (CO2). Anal. Calcd for C23H27O4N (381.48): C, 72.42; H,
7.13; N, 3.67. Found: C, 72.0; H, 7.2; N, 3.3.
(C(4)); 75.4 (C(3)); 172.5 (CO2). HR-MS (Tof ES+) calcd for
C9H18O4N [M+H]+: 204.1236; found: 204.1279.
4.4.9. (2S,3S,4R,5S)-3,4-Dihydroxy-5-methyl-pyrrolidine-2-
acetic acid (1,2,5,6-tetradeoxy-2,5-imino-
acid, 2b)
L-altroheptonic
4.4.6. (2S,3S,4R,5S)-1-Benzyl-3,4-isopropylidenedioxy-5-methyl-
pyrrolidine-2-ethanol (28)
A solution of 27b (100 mg, 0.29 mmol) in aqueous 2 N HCl
(0.9 mL) was stirred at rt for 32 h (NMR monitoring). 5% Pd/C
(20 mg) was then added and the solution hydrogenolysed at rt
for 48 h. The catalyst was centrifuged off and washed with H2O
(0.5 mL). 2b was purified by chromatography with Amberlit
IR120 (H+) resin and eluted successively with H2O, MeOH and
aqueous 0.5 N NH4OH solution. Evaporation of the NH4OH solution
gave pure 2b (26 mg, 62%).
To a solution of 27b (150 mg, 0.39 mmol) in Et2O (1.5 mL) was
added LiAlH4 (23 mg, 0.60 mmol, 1.5 equiv) and the mixture was
stirred at rt for 3 h. Solid Na2SO4ꢀ10H2O (40 mg), Et2O (10 mL)
and aqueous 2.5 N NaOH solution (0.5 mL) were then added and
the mixture was stirred at rt for another 1 h. The solids were fil-
tered out, washed with Et2O and AcOEt, the solvents evaporated.
Purification by FC (Cyclohexane/AcOEt 8:2) gave 28 (101 mg,
89%), characterised by NMR only.
2b: yellowish resin, ½a D20
ꢂ
= ꢁ39 (c 1.0, H2O), Rf = 0.15 (MeOH). IR
28: colourless resin, ½a D20
= ꢁ25 (c 1.0, CHCl3), Rf = 0.08 (Cyclo-
ꢂ
(KBr): 3419, 3248, 1633, 1576, 1405, 1178, 1128, 1048 cmꢁ1
.
1H
hexane/AcOEt 7:3). 1H NMR (400 MHz, CDCl3, 330 K): d 1.28 (d,
3H, Me-5); 1.33 (s, 3H, CH3); 1.35 (dddd, 1H, H-20b); 1.60 (s, 3H,
CH3); 1.66 (ddt, 1H, Ha-20); 3.28 (dq, 1H, H-5); 3.30 (m, 1H, H-2);
3.33 (ddd, 1H, Hb-10); 3.54 (dt, 1H, Ha-10); 3.83, 3.97 (2 d, 2H,
J = 12.8 Hz, CH2Ph); 4.42 (dd, 1H, H-3); 4.60 (dd, 1H, H-4); 7.22–
7.35 (5Har); J(10a,20b) = 5.0, J(10b,20b) = 3.6, J(10a,10b) = 11.0,
J(10a,20a) = 4.6, J(10b,20a) = 9.0, J(20a,20b) = 14.0, J(20a,2) = 8.8,
NMR (400 MHz, D2O): d 1.39 (d, 3H, Me-5); 2.63 (dd, 1H, Hb-20);
2.79 (dd, 1H, Ha-20); 3.72 (dt, 1H, H-2); 3.81 (dq, 1H, H-5); 4.17
(t, 1H, H-4); 4.19 (dd, 1H, H-3); J(20a,20b) = 17.3, J(20a,2) = 4.3,
J(20b,2) = 8.2, J(2,3) = 8.2, J(3,4) = 4.0, J(4,5) = 2.5, J(5,Me) = 6.8 Hz.
13C NMR (100 MHz, D2O): d 11.6 (Me-5); 36.6 (C(20)); 57.1 (C(5));
58.4 (C(2)); 72.1 (C(4)); 75.2 (C(3)); 177.7 (CO2). HR-MS (Tof ES+)
calcd for C7H14NO4 [M+H]+: 176.0923; found: 176.0966.
Hydrochloride 2bꢀHCl: 1H NMR (400 MHz, D2O): d 1.38 (d, 3H,
Me-5); 2.91 (dd, 1H, Hb-20); 3.04 (dd, 1H, Ha-20); 3.78 (dt, 1H, H-
2); 3.81 (dq, 1H, H-5); 4.15 (t, 1H, H-4); 4.23 (dd, 1H, H-3);
J(20a,20b) = 18.2, J(20a,2) = 3.6, J(20b,2) = 6.2, J(2,3) = 9.1, J(3,4) = 3.8,
J(4,5) = 2.6, J(5,Me) = 6.6 Hz.
J(20b,2) = 6.6,
J(2,3) = 1.0,
J(3,4) = 6.2,
J(4,5) = 4.6,
J(5,Me-
5) = 6.8 Hz; 13C NMR (100 MHz, CDCl3): d 11.1 (Me-5); 24.1, 26,3
(CMe2); 29.4 (C20)); 52.2 (CH2Ph); 58.1 (C(5)); 61.3 (C(10)); 64.9
(C(2)); 82.7 (C(4)); 84.9 (C(3)); 111.6 (CMe2); 126.9 (Car-p);
128.3, 129.1 (2Car); 139.5 (Car-s).
4.4.7. (2S,3aS,4S,5R,6S)-6-Methyl-2-phenoxy-hexahydro-
pyrrolo[1,2-b]isoxazole-4,5-diol (29)
4.4.10. (2S,3S,4R,5S)-5-Methyl-3,4-dihydroxy-pyrrolidine-2-
ethanol [1,2,5,6-tetradeoxy-2,5-imino-L-altroheptitol] (2c)
A solution of 26b (0.1 g, 0.34 mmol) in MeOH (0.4 mL) and
aqueous 6 N HCl was stirred for 16 h at rt. Evaporation of the sol-
vent gave crude 29 (90 mg, quant.). It was too unstable to be puri-
fied and was characterised by NMR only.
(a) Directly from the adduct 26a: A solution of 26a (50 mg,
0.2 mmol) in EtOH (1 mL) was hydrogenolysed for 4–5 h over
wet Raney-Nickel (0.5 g). The catalyst was centrifuged off and
washed with EtOH (2 ꢃ 0.5 mL). The combined organic solutions
were agitated at rt for 16 h with 6 N HCl (0.4 mL). The solvent
was evaporated, and 2cꢀHCl (19 mg, 46%) isolated by crystallisation
and washing in iPrOH at 0 °C
29: colourless resin, ½a D20
ꢂ
= +130 (c 1.0, MeOH). IR (KBr): 693,
757, 905, 995, 1050, 1130, 1217, 1492, 1591, 2522, 3348 cmꢁ1
.
1H NMR (400 MHz, D2O): d 1.49 (d, 3H, Me-6); 2.85 (ddd, 1H,
Hb-3); 3.10 (dd, 1H, Ha-3); 4.13 (qd, 1H, H-6); 4.48 (t, 1H, H-5);
4.54 (dd, 1H, H-4); 4.63 (td, 1H, H-3a); 6.55 (d, 1H, H-2); 7.13 (d,
2 Har-o); 7.19 (t, 1 Har-p); 7.42 (t, 2 Har-m); J(2,3b) = 4.8,
J(2,3a) = 0, J(3a,3b) = 13.6, J(3a,H-3a) = 8.1, J(3b,H-3a) = 9.7, J(H-
3a,4) = 7.1, J(4,5) = 3.8, J(5,6) = 2.8, J(6,Me) = 6.8, J(o,m) = 7.4,
J(m,p) = 8.7 Hz. 13C NMR (100 MHz, D2O): d 9.84 (Me-6); 38.5
(C(3)); 69.4 (C(3a)); 69.6 (C(6)); 75.6 (C(4)); 76.2 (C(5)); 107.6
(C(2)); 117.3 (Car-o); 124.3 (Car-p); 130.4 (Car-m); 155.4 (Car-s).
(b) From 28: A stirred solution of 28 (64 mg, 0.23 mmol) in H2O
(0.25 mL) and MeOH (0.25 mL) was hydrolysed for 48 h with 6 N
HCl (0.15 mL) (NMR monitoring). The solvents were evaporated,
H2O (0.8 mL) was added and the solution hydrogenolysed over
5% Pd/C (20 mg) for 24 h at rt. The catalyst was centrifuged off
and the solution passed through Amberlite IR-120 (H+ form).The
resin was eluted with H2O, MeOH and then aqueous 1 N NH4OH
solution. Evaporation of the NH4OH solution gave 2c (35 mg,
quant.).
4.4.8. Ethyl (2S,3S,4R,5S)-3,4-dihydroxy-5-methyl-pyrrolidine-2-
acetate, hydrochloride (ethyl 1,2,5,6-tetradeoxy-2,5-imino-L-
altroheptonate, hydrochloride, 2aꢀHCl)
2c: orange resin, ½a D20
= ꢁ48 (c 1.0, H2O). IR (KBr): 623, 631, 740,
ꢂ
1011, 1038, 1053, 1120, 1161, 1414, 1596, 1632, 2947, 3357 cmꢁ1
.
A solution of 27a (100 mg, 0.30 mmol) in EtOH (1 mL) and aque-
ous 6 N HCl (0.35 mL) was stirred at rt for 32 h (NMR monitoring).
The solvent was evaporated and the residue hydrogenolysed at rt
for 48 h in EtOH (1 mL) over 5% Pd/C (10 mg). The catalyst was cen-
trifuged off and washed with EtOH (0.5 mL), the solvents evapo-
rated. The residue was recrystallised in AcOEt/EtOH 8:2 to give
2aꢀHCl (15 mg, 21%).
1H NMR (400 MHz, D2O): d 1.21 (d, 3H, J = 6.7 Hz, Me-5); 1.80 (m,
1H, Hb-20); 1.97 (m, 1H, Ha-20); 3.29 (m, 1H, H-2); 3.45 (dq, 1H,
J = 2.7, 6.7 Hz, H-5); 3.73 (m, 2H, CH2(10)); 4.02 (m, 2H, H-3, H-4).
13C NMR (100 MHz, D2O): d 13.3 (Me-5); 35.4 (C(20)); 55.5 (C(5));
58.2 (C(2)); 59.7 (C(10)); 73.6 (C(4)); 77.8 (C(3)). HR-MS (Tof ES+)
calcd for C7H16NO3 [M+H]+: 162.1130; found: 162.1166.
Hydrochloride 2cꢀHCl: colourless crystals: mp 163–4 °C. IR (KBr):
993, 1043, 1056, 1229, 1156, 1297, 1334, 1389, 1409, 2948, 3300–
3450 cmꢁ1. 1H NMR (400 MHz, D2O): d 1.37 (d, 3H, Me-5); 1.99 (m,
1H, Hb-20); 2.07 (m, 1H, Ha-20); 3.59 (dq, 1H, H-5); 3.76 (m, 2H,
CH2(10); 3.80 (m, 1H, H-2); 4.15 (t, 1H, H-4); 4.18 (dd, 1H, H-3);
2aꢀHCl: colourless crystals: mp 158–160 °C (AcOEt/EtOH),
½
a 2D0
ꢂ
= ꢁ4 (c 1.0, H2O), Rf = 0.6 (CH2Cl2/EtOH 6:4). IR (KBr): 1011,
1123, 1160, 1214, 1230, 1408, 1634, 1723, 2956, 3408 cmꢁ1 1H
.
NMR (400 MHz, D2O): d 1.29 (t, 3H, CH2CH3); 1.40 (d, 3H, Me-5);
2.92 (dd, 1H, Hb-20); 3.04 (dd, 1H, Ha-20); 3.80 (m, 2H, H-5, H-2);
4.16 (t, 1H, H-4); 4.23 (m, 3H, CH2CH3, H-3); J(5,Me) = 6.8,
J(CH2,CH3) = 7.1, J(20a,2) = 3.5, J(20b,2) = 10.1, J(20a,20b) = 17.8,
J(3,4) = J(4,5) = 3.2 Hz. 13C NMR (100 MHz, D2O): d 11.4 (Me-5);
13.7 (Me); 35.1 (C(20)); 57.2, 57.4 (C(2),C(5)); 63.0 (CH2CH3); 71.9
J(10,20a) = 6.0,
J(10,20b) = 6.2,
J(20a,20b) = 15.0;
J(20a,2) = 4.8,
J(20b,2) = 9.0, J(2,3) = 9.0, J(3,4) = 3.8, J(4,5) = 3.0, J(5,Me) = 6.7 Hz.
13C NMR (100 MHz, D2O): 11.8 (Me-5); 33.0 (C(20)); 57.4 (C(2));
59.2, 59.3 (C(2), (C(10)); 72.1 (C(4)); 76.1 (C(3)).

C. Chevrier et al. / Carbohydrate Research 346 (2011) 1202–1211
1211
J.; Joglar, J.; Delgado, A.; Clapés, P. Chem. Eur. J. 2005, 11, 1392–1401; (f)
Moreno-Clavijo, E.; Carmona, A. T.; Moreno-Vargas, A. J.; Robina, I. Tetrahedron
Lett. 2007, 48, 159–162; (g) Moreno-Clavijo, E.; Carmona, A. T.; Vera-Ayoso, Y.;
Moreno-Vargas, A. J.; Bello, C.; Vogel, P.; Robina, I. Org. Biomol. Chem. 2009, 7,
1192–1202; (h) Behr, J. B. Tetrahedron Lett. 2009, 50, 4498–4501; (i) Calveras,
J.; Egido-Gabás, M.; Gómez, L.; Casas, J.; Parella, T.; Joglar, J.; Bujons, J.; Clapés,
P. Chem. Eur. J. 2009, 15, 7310–7328; (j) Ak, A.; Prudent, S.; Le Nouën, D.;
Defoin, A.; Tarnus, C. Bioorg. Med. Chem. Lett. 2010, 20, 7410–7413.
12. (a) Sifferlen, T.; Defoin, A.; Streith, J.; Le Nouën, D.; Tarnus, C.; Dosbâa, I.;
Foglietti, M.-J. Tetrahedron 2000, 56, 971–978; (b) Schuster, M.; Blechert, S.
Bioorg. Med. Chem. Lett. 2001, 11, 1809–1811; (c) Yasuda, K.; Kizu, H.;
Yamashita, T.; Kameda, Y.; Kato, A.; Nash, R. J.; Fleet, G. W. J.; Molyneux, R.
J.; Asano, N. J. Nat. Prod. 2002, 65, 198–202.
13. Joubert, M.; Defoin, A.; Tarnus, C.; Streith, J. Synlett 2000, 1366–1368. Contrary
to the common opinion, amino-sugars as sulfite adduct as 20 are stable at 0 °C
to ꢁ20 °C for several years when they are pure. We have verified this property
for the sulfite adducts of nojirimycin and fuconojirimycin.10
14. Chevrier, C.; Le Nouën, D.; Neuburger, M.; Defoin, A.; Tarnus, C. Tetrahedron
Lett. 2004, 45, 5363–5366.
4.5. Determination of the fucosidase inhibitor activities
General conditions, see lit.27 with
a-L-fucosidase (EC 3.2.1.51)
from bovine kidney (Km = 0.3 mM, pH 5.5).
Acknowledgements
The support of Ministère de l’Enseignement et de la Recherche
for a Ph.D. Grant to C.C.) is gratefully acknowledged. We also wish
to thank the Université de Haute-Alsace and the École Nationale de
Chimie de Mulhouse for financial support. We thank Mr. Mathias
Wind of Basilea Pharmaceuticals (Basel) for HR-mass spectrometry
measurements. We also thank the students Luc Nachbauer and
Yann Renault for their contribution to this work.
15. Vasella, A. Helv. Chim. Acta 1977, 60, 1273–1295.
16. Duvold, T.; Francis, G. W.; Papaioannou, D. Tetrahedron Lett. 1995, 38, 3153–
3156.
References
17. Karpiesiuk, W.; Banaszek, A. Tetrahedron 1994, 50, 2965–2974.
18. Kocienski, P. J.; Cernigliaro, G.; Feldstein, G. J. Org. Chem. 1977, 42, 1353–1355.
19. Schaefer, J. P.; Higgins, J. G.; Sheney, P. K. Org. Synth. Coll. Vol. 1973, 5, 249–251;
(b) Kiss, J.; D’Souza, R.; van Koeveringe, J. A.; Arnold, W. Helv. Chim. Acta 1982,
65, 1522–1537; (c) Ramasamy, K. S.; Tam, R. C.; Bard, J.; Averett, D. R. J. Med.
Chem. 2000, 43, 1019–1028.
20. Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1982, 47, 276–280.
21. work-up according to Dulphy, H.; Gras, J.-L.; Lejon, T. Tetrahedron 1996, 52,
8517–8524.
1. Fessner, W.-D.; Goße, C.; Jaeschke, G.; Eyrisch, O. Eur. J. Org. Chem. 2000, 125–
132. and references herein.
2. Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–2324.
3. (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–3092; (b)
Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541–560.
4. (a) van der Marel, G. A.; Heskamp, B. M.; Veeneman, G. H.; van Boeckel, C. A. A.;
van Boom, J. H. In Chapleur, W., Ed.; Carbohydrate Mimics, Concept and
Methods; Wiley-VCH, 1998; pp 491–510; (b) de Vries, T.; Knegtel, R. M. A.;
Holmes, E. H.; Macher, B. A. Glycobiology 2001, 11, 119R–128R.
5. Moreno-Clavijo, E.; Carmona, A. T.; Moreno-Vargas, A. J.; Molina, L.; Robina, I.
Curr. Org. Synth. 2011, 8, 102–133.
22. Jensen, H. H.; Jensen, A.; Hazell, G.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2002,
1190–1198.
23. Cicchi, S.; Corsi, M.; Brandi, A.; Goti, A. J. Org. Chem. 2002, 67, 1678–1681.
24. Goti, A.; Cicchi, S.; Cacchiarina, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org.
Chem. 2000, 3633–3645.
25. Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337–1341.
26. Liautard, V.; Alphert, E. C.; Desvergnes, V.; Martin, O. R. J. Org. Chem. 2006, 71,
7337–7345.
27. Behr, J.-B.; Chevrier, C.; Defoin, A.; Tarnus, C.; Streith, J. Tetrahedron 2003, 59,
543–553.
28. Lane, C. F. Synthesis 1975, 135–146.
29. (a) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (b) Confalone, P. N.; Huie, E.
M. Org. React. 1988, 36, 1–173.
30. (a) Bayón, P.; de March, P.; Figueredo, M.; Font, J. Tetrahedron 1998, 54, 15691–
15700; (b) Meske, M. J. Prakt. Chem. 1997, 339, 426–433.
6. Dumas, D. P.; Kajimoto, T.; Liu, K. K.-C.; Wong, C.-H.; Berkowitz, D. B.;
Danishevsky, S. J. Bioorg. Med. Chem. Lett. 1992, 2, 33–36.
7. (a) Fleet, G. W. J.; Shaw, A. N.; Evans, St. V.; Fellows, L. E. J. Chem. Soc., Chem.
Commun. 1985, 841–842; (b) Fleet, G. W. J.; Namgoong, S. K.; Barker, C.; Baines,
S.; Jacob, G. S.; Winchester, B. Tetrahedron Lett. 1989, 30, 4439–4442; (c)
Winchester, B.; Barker, C.; Baines, S.; Jacob, G. S.; Namgoong, S. K.; Fleet, G.
Biochem. J. 1990, 265, 277–282.
8. (a) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 8146–8151; (b) Wishnat, R.; Martin, R.; Takayama, S.;
Wong, C.-H. Bioorg. Med. Chem. Lett. 1998, 8, 3353–3358; (c) Wu, C.-Y.; Chang,
C.-F.; Chen, J. S.-Y.; Wong, C.-H.; Lin, C.-H. Angew. Chem., Int. Ed. 2003, 42, 4661–
4664; (d) Chang, C.-F.; Ho, C.-W.; Wu, C.-Y.; Chao, T.-A.; Wong, C.-H.; Lin, C.-H.
Chem. Biol. 2004, 11, 1301–1306.
9. (a) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter, W. Liebigs Ann. Chem.
1990, 953–963; (b) Legler, G.; Stütz, A. E.; Immich, H. Carbohydr. Res. 1995, 272,
17–30.
10. Dubernet, M.; Defoin, A.; Tarnus, C. Bioorg. Med. Chem. Lett. 2006, 16, 1172–
1174.
31. Chevrier, C.; Defoin, A. Synthesis 2003, 1221–1224.
32. (a) Mizuno, K.; Kimura, Y.; Otsuji, Y. Synthesis 1979, 688; (b) Matysiak, St.;
Fitznar, H. P.; Schnell, R.; Pfleiderer, W. Helv. Chim. Acta 1998, 81, 1545–1566.
33. Bach, P.; Bols, M. Tetrahedron Lett. 1999, 40, 3461–3464.
34. Collins, M.; Travis, A. S. J. Chem. Soc., Perkin 1 1980, 779–786.
35. Erion, M. D.; Ugarkar, B. G.; DaRe, J.; Castellino, A. J.; Fujitaki, J. M.; Dixon, R.;
Appleman, J. R.; Wiesner, J. B. Nucleosides Nucleotides 1997, 16, 1013–1021.
36. Glomb, M. A.; Rösch, D.; Nagaraj, R. H. J. Agric. Food Chem. 2001, 49, 366–372.
37. Sheng, S.-R.; Liu, X.-L.; Wang, X.-C.; Xin, Q.; Song, C.-S. Synthesis 2004, 2833–
2836.
11. (a) Wang, Y.-F.; Dumas, D. P.; Wong, C.-H. Tetrahedron Lett. 1993, 34, 403–406;
(b) Wong, C.-H.; Provencher, L.; Porco, J. A., Jr.; Jung, S.-H.; Wang, Y.-F.; Chen, L.;
Wang, R.; Steensma, D. H. J. Org. Chem. 1995, 60, 1492–1501; (c) Huang, H.;
Wong, C.-H. J. Org. Chem. 1995, 60, 3100–3106; (d) Wong, C.-H.; Dumas, D. P.;
Ishikawa, Y.; Koseki, K.; Danishevsky, S. J.; Weston, B. W.; Lowe, J. B. J. Am.
Chem. Soc. 1992, 114, 7321–7322; (e) Espelt, L.; Bujons, J.; Parella, T.; Calveras,