Stereoselective synthesis of 1,3-disaccharides through diels-alder reactions: Part 2[ ]: Convenient protecting groups for heterodienes and conformational evaluations

Article abstract of DOI:10.1080/07328300902752223

Improved synthesis of 1,3-disaccharides, obtained diastereomerically pure by [4+2] hetero cycloadditions between glycals and -thiono- -keto- -lactones, has been reported. The choice of appropriate protecting groups for -keto- -lactones, stable under cyclo

Full text of DOI:10.1080/07328300902752223

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Stereoselective Synthesis of 1,3-
Disaccharides through Diels-Alder
Reactions: Part 2[ ]: Convenient
Protecting Groups for Heterodienes and
Conformational Evaluations
Gabriele Gabrielli a , Fabrizio Melani b , Sara Bernasconi a , Carlotta
Lunghi a , Barbara Richichi a , Patrick Rollin c , Chiara Venturi a &
Cristina Nativi a
a Dipartimento di Chimica Organica, Universita' di Firenze, via della
Lastruccia 13, Sesto Fiorentino, FI, I-50019, Italy
b Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, via
Ugo Schiff 3, Sesto Fiorentino, FI, I-50019, Italy
c ICOA, UMR Sciences, BP 6759, rue de Chartres, 45067, Orléans
Cedex 2, France
Published online: 01 Apr 2009.
To cite this article: Gabriele Gabrielli , Fabrizio Melani , Sara Bernasconi , Carlotta Lunghi , Barbara
Richichi , Patrick Rollin , Chiara Venturi & Cristina Nativi (2009): Stereoselective Synthesis of 1,3-
Disaccharides through Diels-Alder Reactions: Part 2[ ]: Convenient Protecting Groups for Heterodienes
and Conformational Evaluations, Journal of Carbohydrate Chemistry, 28:3, 124-141
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Journal of Carbohydrate Chemistry, 28:124–141, 2009
ꢀC
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300902752223
Stereoselective Synthesis of
1,3-Disaccharides through
Diels-Alder Reactions: Part 2[1]:
Convenient Protecting Groups
for Heterodienes and
Conformational Evaluations
Gabriele Gabrielli,1 Fabrizio Melani,2 Sara Bernasconi,1
Carlotta Lunghi,1 Barbara Richichi,1 Patrick Rollin,3
Chiara Venturi,1 and Cristina Nativi1
1Dipartimento di Chimica Organica, Universita’ di Firenze, via della Lastruccia 13,
Sesto Fiorentino (FI) I-50019 Italy
2Dipartimento di Scienze Farmaceutiche, Universita’ di Firenze, via Ugo Schiff 3, Sesto
Fiorentino (FI) I-50019 Italy
3ICOA, UMR Sciences – BP 6759, rue de Chartres, 45067 Orle´ans Cedex 2, France
Improved synthesis of 1,3-disaccharides, obtained diastereomerically pure by [4+2] het-
ero cycloadditions between glycals and α-thiono-β-keto-δ-lactones, has been reported.
The choice of appropriate protecting groups for β-keto-δ-lactones, stable under cycload-
dition conditions employed, sensibly shortened the synthesis of heterodienic precursors.
The first example of a β-oxy-imino-δ-lactone synthesized from β-keto-δ-lactones was also
reported. Molecular modeling and conformational evaluations about the cycloaddition
features allowed tentatively rationalizing the experimental results.
Keywords Disaccharides, Diels-alder, Stereoselective synthesis, Conformational
studies
[1]Dedicated to the memory of Prof. Giuseppe Capozzi (1941–2008), Dipartimento di
Chimica Organica, Universita’ di Firenze, who introduced and developed the use of
oxothiones in hetero Diels-Alder reactions.
Address correspondence to Cristina Nativi, Dipartimento di Chimica Organica, Univer-
sita’ di Firenze, via della Lastruccia 13, Sesto Fiorentino (FI) I-50019 Italy. E-mail.
124

Stereoselective Synthesis of 1,3-Disaccharides
125
INTRODUCTION
Enantiopure β-keto-δ-lactones are challenging compounds either as tar-
get molecules[2] or as synthetic precursors to carbohydrate-containing
derivatives.[3] We reported recently the synthesis of enantiopure β-keto-δ-
lactones relying on the chiral pool of carbohydrates and avoiding the forma-
tion of undesired side products.[4] Glucal and galactal derivatives were indeed
transformed into the corresponding β-keto-δ-lactones 1–3, preserving two of
the three original stereocenters (Chart 1).
Besides more “classical” applications, β-keto-δ-lactones can also be used as
effective precursors of electron-poor heterodienes.[5] As a matter of fact, when
OR
O
R'
OR
O
R'
R''
R''
+ PhtNSCl
O
O
O
O
4
1-3
SNPht
1 R' = H, R'' = OBn
5
2
3
R' = H, R'' = OPMB
R' = OBn, R'' = H
Base
OR
R'
O
O
R''
PhtN
R'
=
N
O
O
S
O
6a-c
OPiv
O
BnO
PMBO
PMBO
O
OPiv
O
R
O
O
O
O
O
S
O
O
S
S
O
OBn
BnO
OBn
OBn
OBn
OBn
OBn
OBn
O
10
9
7 R = OBn, R' = H
8 R = H, R' = OBn
OPiv
O
R'
BnO
O
OPiv
R'
OPiv
R
O
R
O
O
O
O
O
O
O
OBn
BnO
BnO
S
OBn
OBn
OBn
BnO
BnO
BnO
O
O
11a R = OBn; R' = H
11b
12
R = OBn, R' = H
13
R = H, R' OBn
14
R = H; R' = OBn
Chart 1: Synthesis of thiones 6a–c and structure of cycloadducts 7–14.

G. Gabrielli et al.
126
treated with phthalimidesulfenyl chloride (4), β-keto-δ-lactones 1–3 gave the
sulfenyl derivatives 5 which, in turn, formed heterodienes 6 by treatment with
weak bases like pyridine or triethylamine[1,6] (Chart 1).
Dienes 6 are highly reactive species that can be trapped in situ with
electron-rich dienophiles. When glycals were employed as dienophiles, 6 re-
acted as glycosyl acceptors to form diastereomerically pure 1,3-disaccharidic
species.[1,6] Since these inverse electron-demand cycloadditions can take place
under mild neutral conditions, several glycals, including exoenitols, were suc-
cessfully employed as starting materials.[1] Cycloadditions occurred with total
chemo- and regioselectivity as well as with high or total diastereoselectivity, af-
fording 2-thio-1,3-disaccharides as diastereomerically pure compounds (7–10)
or as a separable mixture of diastereoisomers (11) (Chart 1).
The presence of a sulfur bridge makes 2-thio-1,3-disaccharides useful pre-
cursors of the corresponding 2,2’-dideoxy disaccharides: treatment of 7–9 with
Raney-nickel afforded indeed diastereomerically pure deoxy disaccharides 12–
14[1] (Chart 1).
RESULTS AND DISCUSSION
Following our interest in the development of β-keto-δ-lactones as glycosyl ac-
ceptors, we report here the synthesis of 4,6-di-O-protected glycal precursors,
taking advantage of convenient protecting groups that allow dramatic simpli-
fication as compared to previously reported synthetic pathways.[1,6] Readily
available unprotected D-glucal and D-galactal were transformed, in one step,
into the corresponding 4,6-O-silyliden-D-glucal and D-galactal 15[7] and 16[7]
or into the 4,6-O-phenylsulfonylethylidene (PSE) glucal 17,[8] (Fig. 1) which
underwent oxidative conversion to afford the desired β-keto-δ-lactones.
Glycals, commercially available as such or as per-O-acetylated derivatives,
are convenient starting material for carbohydrate-containing molecules, com-
mercially available or easily achievable from peracetylated precursors. Selec-
tive protection of glycals, simultaneously at 4- and 6-positions avoiding multi-
ple protection-deprotection steps, continuously receive considerable attention
due to the synthetic versatility of the hydroxyallylic segment.[9] However, the
Si
O
Si
O
PSE
O
O
O
O
O
O
O
HO
HO
HO
15
17
16
Figure 1: Structures of 4,6-di-O-protected D-glycals 15–17.

Stereoselective Synthesis of 1,3-Disaccharides
127
choice of effective protection is sometimes tricky: acid-catalyzed introduction
of protecting groups can be disappointing due to the production of variable
quantities of rearranged structures (Ferrier rearrangement). This is the case
for benzylidene acetal. A better alternative to a benzylidene acetals is the p-
methoxybenzylidene acetal, which can be introduced under milder conditions[9]
but which is more labile. Other options, such as siloxanylidene acetal,[9] are
reported; however, those are often formed in low yield or with moderate regios-
electivity, especially in the case of galactal.
In order to access 4,6-O-protected glycals more conveniently than previ-
ously reported, the synthesis of 4,6-O-di-(tert-butyl)silylidene-D-glycals was
successfully realized following the strategy reported by Hoberg.[7a] The re-
action was performed under very mild conditions (–40◦C, 30 min) using di-
tert-butylsilyl ditriflate in DMF to produce the 4,6-O-protected D-glucals 15
and the 4,6-O-protected D-galactal 16 in 96% and 83% yield, respectively
(Fig. 1). Silylidene glycals 15 and 16 are stable derivatives that can be pu-
rified by column chromatography on silica gel. After regioselective hydration
of the double bond,[10] dihydroxyderivatives 18 and 19 were oxidized with
Fetizon reagent[11] to give lactones 20 and 21 (Sch. 1). Subsequent oxida-
tion of the C-3 hydroxyl group allowed conversion of 20 and 21 into the de-
sired β-keto-δ-lactones 22 and 23, the direct precursors of α-thiono-β-keto-δ-
lactones 24 and 25. Heterodienes 24 and 25, obtained as reported in Scheme
1, were trapped in situ with 3,4,6-tri-O-benzyl-D-glucal, affording the ex-
pected 1,3-disaccharides 26 (39%–60% over two steps) and 27 (21%–57% over
two steps) (see Experimental section), respectively, as single diastereoisomers
(Sch. 1).
Although the oxidation of lactones 20 and 21 to β-ketolactones 22 and 23
could acceptably be performed under Swern conditions,an improvement was
represented by employing o-iodoxybenzoic acid (IBX) as oxidant.[12] Indeed,
treatment of 20 and 21 with freshly prepared IBX[13] in ethyl acetate produced
1
ketolactones 22 (75%, on the basis of H NMR spectra) and 23 (65%, on the
1
basis of H NMR spectra), which were used, without purification for conver-
sion into the corresponding thiones 24 and 25 (see Experimental section) (Sch.
1). On the contrary, when using Swern conditions, isolation/purification of ke-
tolactones caused a drop of cycloaddition yields. In fact, the complex reaction
mixtures were more conveniently treated with phthalimidosulfenyl chloride
without purification (see Experimental section).
Deprotection of the 4,6-silylidene derivative 26 was successfully performed
under standard conditions (TBAF, DMF) to afford disaccharide 28[1] in 71%
yield (Sch. 1). Another convenient protection strategy for D-glucal relies on
the formation of 4,6-O-phenylsulfonylethylidene (PSE) acetal.[8] The 4,6-O-
phenylsulfonylethylidene glucal 17 (Fig. 1), obtained, under basic conditions,
following a reported procedure[14]; was subsequently transformed, as above de-
scribed for 22 and 23, into the corresponding thione 29 (Sch. 2); and the latter

G. Gabrielli et al.
128
Si
O
Si
Si
O
O
O
(a)
O
O
(b)
O
(c) or (d)
O
O
15
O
HO
OH
HO
O
O
18
22
20
Si
Si
Si
O
O
O
O
O
O
O
O
(c) or (d)
(b)
O
(a)
16
HO
HO
OH
O
O
O
21
19
23
HO
HO
Si
O
O
O
O
Si
O
O
O
(e)
(g)
(f)
O
O
S
22
O
O
S
OBn
O
O
O
OBn
OBn
OBn
OBn
OBn
S
O
24
26
28
Si
O
Si
O
O
(e)
(f)
O
O
23
O
O
O
O
S
O
OBn
OBn
OBn
S
O
25
27
Scheme 1: Reagents and conditions: (a) (i) NIS, H2O, CH3CN, rt, 25–45 min; (ii) NaHCO3,
Na2S2O4, THF, rt, 3–4 h, 82% (18), 83% (19); (b) Fetizon reagent, benzene, reflux, 3–20 h, 76%
(20), 88% (21); (c) DMSO, trifluoroacetic anhydride, CH2Cl2, –60/–30◦C, 1.5 h; (d) IBX, EtOAc,
80◦C, 2.5–3.5 h; (e) PhtNSCl, CHCl3, Py, rt, 15 min; (f) 3,4,6-Tri-O-benzyl-D-glucal, 60◦C, 22 h–3
d, 39% or 60% over two steps (26), 21% or 57% over two steps (27); (g) TBAF, DMF, rt, 1.5 h, 71%.
trapped with 3,4,6-tri-O-benzyl-D-glucal to give 1,3-disaccharide 30, as a sin-
gle diastereoisomer, albeit in poor yield (17%).[15]
With a view to accessing N-1,3-disaccharides starting from β-keto-δ-
lactones as enantiopure material, lactone 3 was converted into the N-protected
β-oxy-imino-δ-lactone 31 under standard conditions as reported in Scheme 2.
Sulfonyloxyimino derivative 31 was reacted in chloroform with phthalimido
sulfenylchloride and the crude treated with 3,4,6-tri-O-benzyl-D-glucal and
pyridine. Since no cycloadduct was detected at rt, different reaction conditions
were employed (40◦C, 60◦C/1–5 days, DBU or lutidine, DMF as solvent) but
without improvement.
Although effective, cycloadditions to form 26, 27, and 30 appeared quite
sluggish with respect to those reported to prepare 7–11,[1] and moreover, no

Stereoselective Synthesis of 1,3-Disaccharides
129
PSE
O
PSE
(a)
O
PSE
O
17
O
O
(c)
(b)
O
O
O
O
HO
OH
O
HO
O
O
33
34
(d)
PSE
O
O
O
S
PSE
O
(e)
O
O
O
O
O
O
OBn
OBn
OBn
S
O
29
30
OPiv
O
OPiv
O
BnO
N
BnO
(g)
(f)
3
O
O
N
O
O
S
SO2Ph
31
SO2Ph
32
Scheme 2: Reagents and conditions: (a) 8N HCl, dioxane, rt, 1.5 h, 78%; (b) Fetizon reagent,
benzene, 80◦C, 10 h, 58%; (c) DMSO, trifluoroacetic anhydride, CH2Cl2, –60/–30◦C, 2.5 h; (d)
PhtNSCl, CHCl3, Py, rt, 15 min; (e) 3,4,6-Tri-O-benzyl-D-glucal, 60◦C, 54 h, 17% over two steps;
(f) (i) hydroxylamine hydrochloride, H2O, sodium acetate, i-PrOH, rt, 12 h, 97%; (ii) Et3N,
benzenesulfonyl chloride, DMAP, CH2Cl2, 0◦C, 1 h, 18%; (g) PhtNSCl, CHCl3, Py, rt.
cycloaddition at all took place in the case of α-thiono-β-oxy-imino lactone 32.
For compounds 26, 27, and 30 we hypothesized a possible consequence of the
bicyclic structure of the thiones implicated: due to ring constraint, those could
present the C=O and the C=S groups involved in the cycloaddition, orien-
tated with dihedral angles sensibly far from 0◦, that is in an unfavorable
conformation for a reactive Diels-Alder heterodiene. In order to try and ver-
ify this hypothesis and rationalize the experimental data, dynamic molecular
calculations (DISCOVER, cff91 Force Field)[16] on thiones 24, 25, 29, and 32
were carried out. Statistical analysis of O=C-C=S dihedral angles’ distribu-
tion, measured in the collected conformation during trajectory simulation at
293◦K, showed Gaussian-like distributions (frequency vs. O=C-C=S dihedral
Table 1: Dihedral angles of thiones 24, 25, 29, and 32 and ꢀE of cycloadditions.
Diene
Dihedral Angle C=O/C=S (◦)a
ꢀE (eV) (HOMO-LUMO)b
24
25
29
32
+25.4
−2.5
+23.5
+49
7.28
7.43
7.00
7.74
a Calculated at 293◦K.
b HOMO of dienophile (3,4,6-tri-O-benzyl-D-glucal) = –9.37 eV.

G. Gabrielli et al.
130
Table 2: Statistical analysis of O=C-C=S dihedral angles’ distribution (frequency vs.
angles) for diene 24, 25, 29, and 32 at 293◦K (A) and 353◦K (B).
210
180
150
120
90
210
180
150
120
90
60
60
30
30
0
0
-100 -80 -60 -40 -20
0
20 40 60 80 100
-100 -80 -60 -40 -20
0
20 40 60 80 100
24 (A)
24 (B)
180
150
120
90
180
150
120
90
60
60
30
30
0
0
-100 -80 -60 -40 -20
0
20 40 60 80 100
-100 -80 -60 -40 -20
0
20 40 60 80 100
25 (A)
25 (B)
240
210
180
150
120
90
240
210
180
150
120
90
60
60
30
30
0
0
-100 -80 -60 -40 -20
0
20 40 60 80 100
-100 -80 -60 -40 -20
0
20 40 60 80 100
29 (B)
29 (A)
300
270
240
210
180
150
120
90
300
270
240
210
180
150
120
90
60
60
30
30
0
0
-100 -80 -60 -40 -20
0
20 40 60 80 100
-100 -80 -60 -40 -20
0
20 40 60 80 100
32 (A)
32 (B)

Stereoselective Synthesis of 1,3-Disaccharides
131
angles) with a maximum frequency ranging between –20◦÷20◦. As a matter of
fact, the low energetic conformers appear to display C=O/C=S dihedral angles
ranging from –2.5◦ (25) to 25.4◦ (24) (Table 1).
The distribution appeared less spread for data obtained at 353◦K. In
Table 2 are reported the histograms referred to the two data sets for each
diene.
Perturbing the molecules so that dihedral angles become 0◦ creates re-
active conformations for cycloadditions about 0.1 to 0.5 kcal/mol less stable.
Thus, a reactive geometry for cycloadditions might be reached at rt. However,
the energy gap of the molecular orbitals involved in the cycloadditions, that
is, the HOMO of the dienophile (3,4,6-tri-O-benzyl-D-glucal) and the LUMO
of dienes (24, 25, 29), ranges between 7.6 and 7.9 eV (AM1 semiempirical cal-
culations), which corresponds to a moderate or slow apparent rate.[17] Steri-
cal hindrance offered by PSE and silylidene protecting groups in bicyclic lac-
tones likely influences the cycloaddition rate as well: indeed, those groups
might negatively affect the reactive approach of dienophile and heterodienes
on parallel planes. In the case of the N-sulfonyloxyimine 32 the low ener-
getic conformer is shown to have the oxyimino and thiocarbonyl groups ori-
ented with a dihedral angle of about 49◦ (Table 1) with a frequency next to
zero for angles in the −20◦÷20◦ range, at 293 as well as 353◦K. Moreover,
the reactive conformation for cycloaddition is about 5 kcal/mol less stable (see
Table 1).[18]
CONCLUSION
In conclusion, enantiopure 4,6-di-O-protected β-keto-δ-lactones can be ef-
ficiently synthesized from glycals avoiding tedious and time-consuming
protection-deprotection reactions. We used both silylidene and PSE protecting
groups, which we demonstrated are stable under reaction conditions em-
ployed to form 1,3-disaccharides following the cycloaddition way we propose.
Silylidene-lactones 22 and 23 were transformed into the corresponding thiones
24 and 25 and profitably reacted as heterodienes in inverse electron-demand
cycloadditions affording 2-thio-1,3-disaccharides 26 and 27. PSE-protected
disaccharide 30 was synthesized as well, although in lower yield. The energy
gap between the molecular orbitals involved in the cycloadditions and sterical
hindrance of heterodienes’ protecting groups likely explain the moderate yields
observed. The synthesis of β-oxy-imino-δ-lactone 31 from β-keto-δ-lactone 3
was reported as well. The cycloaddition approach to 1,3-disaccharides, al-
though with satisfactorily yields, is confirmed synthetically attractive since
disaccharides are formed diasteromerically pure, relying on a short and simple
sequence. The latter versatile, polyfunctionalized saccharidic structures are
under current investigations in our laboratories.

G. Gabrielli et al.
132
EXPERIMENTAL
4,6-Di-O-tert-butylsilylidene-D-glucal (15)
To a stirred solution of D-glucal (2.19 g, 15.0 mmol) in dry DMF (60 mL)
cooled to –40◦C, di-tert-butylsilyl bis(trifluoromethanesulfonate) (6.02 mL, 16.5
mmol) was added dropwise in 15 min. The solution was stirred at –40◦C for 30
min and then Py (1.46 mL, 18.0 mmol) was added. After 5 min the solution was
diluted with Et2O (300 mL) and washed with a saturated solution of NaHCO3
(1 × 75 mL) and H2O (2 × 75 mL). The organic phase was dried over Na2SO4
and evaporated under reduced pressure. The crude was purified by flash col-
umn chromatography on silica gel (petroleum ether:ethyl acetate = 4:1, Rf =
1
0.6) to afford 15 (4.14 g, 96%) as a white solid. m.p.= 81–83◦C; H NMR (400
MHz, CDCl3): δ 6.25 (dd, J = 6.0 Hz, J = 2.0 Hz, 1H), 4.75 (dd, J = 6.0 Hz,
J = 2.0 Hz, 1H), 4.29 (bd, J = 2.8 Hz, 1H), 4.17 (dd, J = 4.8 Hz, J = 10.0 Hz,
1H), 3.98–3.86 (m, 2H), 3.81 (m, 1H), 2.49 (d, J = 2.8 Hz, 1H), 1.06 (s, 9H), 0.98
(s, 9H); 13C NMR (75 MHz, CDCl3): δ 143.6, 103.0, 77.4, 72.3, 70.2, 65.7, 27.5,
26.9, 22.8, 19.9.
4,6-O-Di-tert-butylsilylidene-D-galactal (16)
To a stirred solution of D-galactal (500 mg, 3.4 mmol) in dry DMF (13 mL)
cooled to –40◦C, di-tert-butylsilyl bis(trifluoromethanesulfonate) (1.2 mL, 3.8
mmol) was added dropwise in 15 min. The solution was stirred at –40◦C for 1.5
h and then Py (0.33 mL, 4.1 mmol) was added. After 5 min the solution was
diluted with Et2O (40 mL) and washed with a saturated solution of NaHCO3 (1
× 15 mL) and water (2 × 15 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The crude was purified by flash column
chromatography on silica gel (petroleum ether:ethyl acetate = 6:1, Et3N [5%],
Rf = 0.4) to afford 16 (642 mg, 72%) as a with solid. m.p.= 103–105◦C; 1H NMR
(200 MHz, CDCl3): δ 6.29 (dd, J1−2 = 6.6 Hz, J1−3 = 1.4 Hz, 1H), 4.72–4.69 (m,
1H), 4.41–4.26 (m, 2H), 4.25–4.23 (m, 2H), 3.86 (bs, 1H), 2.75 (d, JOH−3 = 11.0
Hz, 1H), 1.06 (s, 9H), 1.00 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 143.9, 103.3,
73.3, 68.6, 67.4, 63.7, 27.6, 27.0, 23.4, 20.9.
4,6-O-(2-Phenylsulfonyl)ethylidene-D-glucal (17)
To a suspension of D-glucal (1.34 g, 9.18 mmol) in dry THF (90 mL), cooled
to 0◦C, a catalytic amount of TBAB and NaH (95%, 463 mg, 18.36 mmol) was
added. The mixture was stirred for 15 min, BPSE (2.83 g, 9.18 mmol) was
added, and the mixture was warmed to rt and stirred for additional 12 h. The
mixture was treated with brine (30 mL) and diluted with EtOAc (70 mL) and
the two phases were separated. The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The crude was purified by flash column

Stereoselective Synthesis of 1,3-Disaccharides
133
chromatography on silica gel (petroleum ether:ethyl acetate = 1:1, Rf = 0.3) to
afford 17 (2.00 g, 70%) as colorless oil. [α]2D5 = + 18 (c 1.4, CHCl3); H NMR
1
(250 MHz, CDCl3): δ 7.92–7.95 (m, 2H), 7.55–7.51 (m, 3H), 6.25 (dd, J = 6.2
Hz, J = 2.1 Hz, 1H), 5.10–4.98 (X part of an A2X system, JX−A = 4.9 Hz, 1H),
4.69 (dd, 1H, J = 6.2 Hz, J = 2.1 Hz, 1H), 4.21 (dt, J = 2.1 Hz, J = 7.1 Hz, 1H),
4.13 (dd, J = 3.5 Hz, J = 9.4 Hz, 1H), 3.64 (dd, J = 4.61 Hz, J = 9.4 Hz, 1H),
3.54–3.50 (A2 part of an A2X, JA−X = 4.9 Hz, 1H), 3.45–3.61 (m, 2H); 13C NMR
(50 MHz, CDCl3): δ 144.4, 140.1, 134.5, 128.8, 103.8, 97.2, 78.7, 66.2, 66.1, 64.5,
58.2.
4,6-O-Di-tert-butylsililydene-2-deoxy-D-glucopyranose (18)
To a stirred solution of 15 (300 mg, 1.04 mmol) in CH3CN (8 mL), cooled to
0◦C, H2O (400 µL) and NIS (259 mg, 1.15 mmol) were added. The reaction mix-
ture was then warmed to rt and stirred in the dark. After 45 min the solvent
was removed under reduced pressure and the crude was dissolved in THF (10
mL). A solution of NaHCO3 (1M, 10.4 mL) and Na2S2O4 (724 mg, 4.16 mmol)
were then added and the reaction mixture was stirred at rt for 3 h. The mixture
was then diluted with EtOAc (70 mL) and washed with phosphate buffer (pH
= 7) (1 × 5 mL) and H2O (2 × 5 mL). The organic phase was dried over Na2SO4
and evaporated under reduced pressure. The crude was purified by flash col-
umn chromatography on silica gel (petroleum ether:ethyl acetate = 2:1, Rf =
0.4) to afford 18 (258 mg, 82%) as a white solid. m.p.= 135–137◦C; Anal. Calcd
for C14H24O5Si: C, 55.23; H, 9.27. Found: C, 54.78; H, 9.32. 1H NMR (400 MHz,
CDCl3): δ 5.33 (dd, J = 3.0 Hz, 1H), 4.91 (ddd, J = 2.0 Hz, J = 9.2 Hz, J =
6.8 Hz, 1H), 4.15 (dd, J = 10.0 Hz, J = 5.2 Hz, 1H), 4.06 (dd, J = 9.6 Hz, J =
4.8 Hz, 1H), 4.03–3.99 (m, 1H), 3.98–3.89 (m, 2H), 3.84 (dd, J = 9.6 Hz, 1H),
3.70–3.64 (m, 1H), 3.63–3.58 (m, 2H), 3.38 (ddd, J = 5.2 Hz, J = 9.2 Hz, J =
10.0 Hz, 1H), 3.29 (d, J = 6.8 Hz, 1H), 2.76–2.71 (m, 3H), 2.34 (ddd, J = 12.8
Hz, J = 4.8 Hz, J = 2.0 Hz, 1H), 2.20 (ddd, J = 13.2 Hz, J = 5.2 Hz, J = 1.2
Hz, 1H), 1.73–1.66 (m, 1H), 1.62–1.54 (m, 1H), 1.06 (s, 9H), 1.05 (s, 9H), 1.00
(s, 9H), 0.98 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 94.5, 92.4, 79.7, 78.8, 68.4,
66.6, 66.5, 71.2, 70.6, 66.2, 39.2, 36.5, 27.4, 26.9, 22.7, 19.7.
4,6-O-Di-tert-butylsilylidene-2-deoxy-D-galactopyranose (19)
To a stirred solution of 16 (176 mg, 1.7 mmol) in CH3CN (13.0 mL), cooled
to 0◦C, H2O (700 µL) and NIS (411 mg, 1.8 mmol) were added. The reaction
mixture was then warmed to rt and stirred in the dark. After 25 min the sol-
vent was evaporated under reduced pressure and the crude was dissolved in
THF (16.6 mL). A solution of NaHCO3 (1M, 16.6 mL) and Na2S2O4 (1.15 g,
6.6 mmol) were then added and the reaction mixture was stirred at rt for
4 h. The mixture was then diluted with EtOAc (50 mL) and washed with H2O

G. Gabrielli et al.
134
(1 × 5 mL) and brine (1 × 5 mL). The organic phase was dried over Na2SO4,
and evaporated under reduced pressure. The crude was purified by flash chro-
matography on silica gel (petroleum ether:ethyl acetate = 3:2, Rf = 0.4) to af-
ford 19 (423 mg, 83%) as a colorless oil. Anal. Calcd for C14H24O5Si: C, 55.23;
1
H, 9.27. Found: C, 54.69; H, 9.32. H NMR (400 MHz, CDCl3): δ 5.4 (bs, 1H),
4.74 (ddd, J = 2.0 Hz, J = 9.6 Hz, J = 6.4 Hz, 1H), 4.31 (d, J = 2.8 Hz, 1H),
4.28 (dd, J = 12.4 Hz, J = 2.4 Hz, 1H), 4.27 (dd, J = 12.4 Hz, J = 2.0 Hz,
1H), 4.23 (dd, J = 12.4 Hz, J = 1.6 Hz, 1H), 4.22 (d, J = 3.2 Hz, 1H), 4.12
(dd, J = 12.4 Hz, J = 1.6 Hz, 1H), 4.055–3.977 (m, 1H), 3.91–3.90 (m, 1H),
3.7–3.64 (m,1H), 3.40 (d, J = 6.4 Hz, 1H), 3.36–3.35 (m, 1H), 2.91–2.90 (m,
1H), 2.61 (d, J = 11.2 Hz, 1H), 2.47 (d, J = 11.6 Hz, 1H), 2.09 (ddd, J = 12.0
Hz, J = 4.8 Hz, J = 2.0 Hz, 1H), 1.97–1.82 (m, 2H), 1.76–1.68 (m, 1H), 1.06
(s, 9H), 1.05 (s, 18H), 1.03 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 94.5, 92.4,
71.9, 71.7, 70.6, 68.8, 67.6, 67.2, 67.1, 36.5, 33.1, 27.7, 27.6, 27.4, 27.2, 23.3,
20.8.
4,6-O-Di-tert-butylsilylidene-2-deoxy- D-arabino-1,
5-hexonolactone (20)
To a solution of 18 (210 mg, 0.68 mmol) in dry benzene (14 mL), freshly
prepared Fetizon’s reagent (2.20 g, 4.44 mmol) was added. The mixture was
warmed to 80◦C and refluxed for 20 h, then cooled to rt, diluted with EtOAc,
and filtered through a pad of Celite. The solvent was evaporated under reduced
pressure, and the crude was purified by flash column chromatography on silica
gel (petroleum ether:ethyl acetate = 2:1, Rf = 0.5) to afford 20 (160 mg, 76%)
as a white solid. [α]2D5 = + 8 (c 0.52, CHCl3); m.p.= 108–110◦C; Anal. Calcd for
1
C14H26O5Si: C, 55.60; H, 8.26. Found: C, 55.95; H, 8.98. H NMR (400 MHz,
CDCl3): δ 4.26 (dd, J = 10.0 Hz, J = 4.8 Hz, 1H), 4.11–4.05 (m, 1H), 4.01–3.85
(m, 3H), 3.13 (dd, J = 18.2 Hz, J = 7.2 Hz, 1H), 2.78 (bs, 1H), 2.60 (dd, J = 18.2
Hz, J = 9.6 Hz, 1H), 1.07 (s, 9H), 0.99 (s, 9H); 13C NMR (50 MHz, CDCl3): δ
167.7, 76.7, 72.7, 68.9, 65.5, 36.7, 27.3, 26.9, 22.6, 19.8.
4,6-O-Di-tert-butylsilylidene-2-deoxy- D-lyxo-1,5-hexonolactone
(21)
To a solution of 19 (750 mg, 2.46 mmol) in dry benzene (50 mL), freshly pre-
pared Fetizon’s reagent (5.54 g, 9.85 mmol) was added. The mixture was heated
to 80◦C and refluxed for 3 h, then cooled to rt, diluted with EtOAc, and filtered
through a pad of Celite. The solvent was evaporated under reduced pressure
to afford 21 (657 mg, 88%) as a colorless oil. [α]2D5 = +3 (c 0.33, CHCl3); Anal.
Calcd for C14H26O5Si: C, 55.60; H, 8.26. Found: C, 55.17; H, 8.84. 1H NMR (400
MHz, CDCl3): δ 4.57–4.56 (m, 1H), 4.41–4.32 (m, 2H), 4.19–4.18 (m, 1H), 4.06–
4.01 (m, 1H), 2.93 (dd, J = 17.6 Hz, J = 6.6 Hz, 1H), 2.66 (dd, J = 17.6 Hz,

Stereoselective Synthesis of 1,3-Disaccharides
135
J = 10.4 Hz, 1H), 2.63 (d, JOH−3 = 10.4 Hz, 1H), 1.09 (s, 9H), 1.00 (s, 9H); 13C
NMR (50 MHz, CDCl3): δ 169.4, 75.5, 70.0, 66.9, 66.4, 35.1, 27.6, 26.9, 23.3,
20.7
Cycloadduct 26
Procedure A: To a mixture of dry DMSO (0.49 mL, 6.95 mmol) and dry
CH2Cl2 (3 mL), cooled to –78◦C, trifluoroacetic anhydride (0.28 mL, 1.98 mmol)
was added dropwise under vigorous stirring. The suspension obtained was
warmed to –60◦C and a solution of 20 (100 mg, 0.331 mmol) in dry CH2Cl2
(1.1 mL) was added. The mixture was stirred for 1 h at –60◦C, and then Et3N
(0.55 mL, 3.97 mmol) was added and the temperature was allowed to warm
to –30◦C. After 30 min the mixture was diluted with CH2Cl2 (30 mL) and
washed with a saturated solution of NH4Cl (1 × 10 mL). The organic phase
was dried over Na2SO4 and evaporated under reduced pressure to a complex
reaction mixture that was diluted in CHCl3(6 mL) and treated with solid Ph-
tNSCl (70.5 mg, 0.331 mmol). The mixture was stirred at rt for 15 min, and
then 3,4,6-tri-O-benzyl-D-glucal (138 mg, 0.331 mmol) and Py (0.26 mL, 3.31
mmol) were added and the mixture was warmed to 40◦C, then stirred for 15
h. The mixture was diluted with CHCl3(40 mL) and washed with a saturated
solution of NH4Cl (2 × 10 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The crude was purified by flash column
chromatography on silica gel (petroleum ether:ethyl acetate = 3:1, Rf = 0.3)
to afford 26 (96 mg, 39% over two steps) as a yellow solid. Procedure B: To a
solution of 20 (100 mg, 0.33 mmol) in dry EtOAc (5 mL), IBX (640 mg, 2.31
mmol) was added under nitrogen. The mixture was stirred to 80◦C, stirred
for 2.5 h, and then cooled to 0◦C, and then diluted with EtOAc (30 mL) and
filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure to dryness to give 106 mg of a mixture of 22 (74 mg, 0.25 mmol, 75%,
1
on the basis of H NMR spectra), 20 (15 mg, 0.05 mmol) and 2-iodo-benzoic
acid (17 mg, 0.07 mmol). To a solution of the crude mixture in dry CHCl3 (4
mL), PhtNSCl (53 mg, 0.247 mmol) was added and the reaction was stirred
for 15 min at rt. 3,4,6-Tri-O-benzyl-D-glucal (103 mg, 0.247 mmol) and Py (1
mL) were then added and the mixture was warmed to 60◦C and stirred for 22
h. The mixture was then diluted with CHCl3 (40 mL) and washed with a satu-
rated solution of NH4Cl (2 × 10 mL). The organic phase was dried over Na2SO4
and evaporated under reduced pressure. The crude was purified by flash col-
umn chromatography on silica gel (petroleum ether:ethyl acetate = 6:1, Rf =
0.4) to afford 26 (112 mg, 60%) as a pale yellow solid. [α]2D5 = + 126 (c 1.07,
CHCl3); m.p.= 77–78◦C; Anal. Calcd for C41H50O9SSi; C, 65.92; H, 6.75. Found:
C, 65.95; H, 6.91. ESI MS: 747.4 ([MH]+), 769.4 ([M+Na]+), 785.3 ([M+K]+).
1H NMR (400 MHz, CDCl3): δ 7. 35–7.22 (m, 15H), 5.77 (d, J = 3.2 Hz, 1H),
4.92–4.89 (A part of an AB system, JA−B = 12.0 Hz, 1H), 4.87–4.84 (A part

G. Gabrielli et al.
136
of an AB system, JA−B = 11.2 Hz, 1H), 4.84–4.81 (B part of an AB system,
JB−A = 11.2 Hz, 1H), 4.74 (d, J4−5 = 10.4 Hz, 1H), 4.65–.73 (B part of an AB
system, JB−A = 12.0 Hz, 1H), 4.62–4.59 (A part of an AB system, JA−B = 12.0
Hz, 1H), 4.53–4.50 (B part of an AB system, JB−A = 12.0 Hz, 1H), 4.22 (dd,
J = 5.2 Hz, J = 10.4 Hz, 1H), 4.07 (at, J = 10.4 Hz, 1H), 4.02–3.98 (m, 1H),
3.89–3.82 (m, 1H), 3.74 (dd, J = 3.2 Hz, J = 10.8 Hz, 1H), 3.70 (dd, J = 2.0
Hz, J = 10.8 Hz, 1H), 3.60 (dd, J = 10.8 Hz, J = 8.8 Hz, 1H), 3.27 (dd, J = 3.2
Hz, J = 10.8 Hz, 1H), 1.07 (s, 9H), 0.96 (s, 9H); 13C NMR (50 MHz, CDCl3): δ
162.2, 160.7, 138.2, 137.5, 137.0, 129.2, 128.2, 127.8, 127.3, 127.0, 97.2, 93.7,
78.7, 75.3, 75.1, 74.3, 73.4, 73.3, 73.1, 69.8, 67.8, 65.2, 42.3, 27.3, 27.0, 22.8,
20.1.
Cycloadduct 27
Procedure A: To a mixture of dry DMSO (0.97 mL, 13.73 mmol) and dry
CH2Cl2 (3.3 mL), cooled to –78◦C, trifluoroacetic anhydride (0.55 mL, 3.92
mmol) was added dropwise under vigorous stirring. The suspension obtained
was warmed to –60◦C and a solution of 21 (198 mg, 0.65 mmol) in dry CH2Cl2
(7 mL) was added. The mixture was stirred for 1 h at –60◦C, and then Et3N
(1.09 mL, 7.85 mmol) was added and the temperature was allowed to reach –
30◦C. After 1 h the mixture was diluted with CH2Cl2 (30 mL) and washed with
a saturated solution of NH4Cl (2 × 10 mL). The organic phase was dried over
Na2SO4 and evaporated under reduced pressure to give a complex mixture
that was dissolved in CHCl3(8 mL) and the solution obtained treated with Ph-
tNSCl (142 mg, 0.65 mmol). The mixture was stirred at rt for 15 min, and then
3,4,6-tri-O-benzyl-D-glucal (272 mg, 0.65 mmol) and Py (2 mL) were added
and the mixture was heated to 60◦C for 36 h. The mixture was then diluted
with CHCl3(40 mL) and washed with a saturated solution of NH4Cl (2 × 10
mL). The organic phase was dried over Na2SO4 and evaporated under reduced
pressure. The crude was purified by flash column chromatography on silica gel
(PE:EtOAc = 3:2, Rf = 0.5) to afford 27 (95 mg, 21%) as a yellow solid. Proce-
dure B: To a solution of 21 (190 mg, 0.63 mmol) in dry AcOEt (6.5 mL), IBX
(1.59 g, 5.69 mmol) was added under N2 atm. The mixture was heated to 80◦C,
stirred for 3.5 h, and then cooled to 0◦C; diluted with AcOEt (200 mL); and
filtered through a pad of Celite. The filtrate was concentrated under reduced
pressure to dryness to give 199 mg of a crude mixture of 23 (123 mg, 0.41 mmol,
65%, on the basis of 1H NMR spectra), 21 (54 mg, 0.18 mmol), and 2-I-benzoic
acid (22 mg, 0.09 mmol). To a solution of this three-component crude mixture
in dry CHCl3 (5.0 mL), PhtNSCl (87 mg, 0.41 mmol) was added; the reaction
was stirred for 15 min at rt. 3,4,6-Tri-O-benzyl-D-glucal (171 mg, 0.41 mmol)
and pyridine (5 mL) were then added and the mixture was heated to 60◦C and
stirred for 3 d. The mixture was then diluted with CHCl3 (40 mL) and washed
with a saturated solution of NH4Cl (2 × 10 mL). The organic phase was dried

Stereoselective Synthesis of 1,3-Disaccharides
137
over Na2SO4 and evaporated under reduced pressure. The crude was purified
by flash column chromatography on silica gel (PE:EtOAc = 3:2, Rf = 0.5) to af-
ford 27 (175 mg, 57%) as a pale yellow solid. [α]2D5 = +0.3 (c 0.27, CHCl3); m.p.=
67–68◦C; Anal. Calcd for C41H50O9SSi; C, 65.92; H, 6.75. Found: C, 65.84; H,
6.79. ESI MS: 747.4 ([MH]+), 769.4 ([M+Na]+), 785.3 ([M+K]+); 1H NMR (400
MHz, CDCl3): δ 7.38–7.27 (m, 12H), 7.20–7.17 (m, 3H), 5.70 (d, J = 2.6 Hz, 1H),
4.89–4.88 (A part of an AB system, J = 10.5 Hz, 1H), 4.88–4.85 (A part of an AB
system, J = 10.6 Hz, 1H), 4.83–4.81 (B part of an AB system, J = 10.5 Hz, 1H),
4.68–4.62 (A part of an AB system, J = 12.2 Hz, 1H), 4.59–4.54 (B part of an AB
system, J = 10.6 Hz, 1H), 4.58–4.52 (B part of an AB system, J = 12.2 Hz, 1H),
4.48 (d, J = 2.3 Hz, 1H), 4.38 (dd, J = 1.9 Hz, J = 13.1 Hz, 1H), 4.30 (dd, J =
1.9 Hz, J = 13.1 Hz, 1H), 4.06–4.04 (m, 1H), 4.02–3.98 (m, 1H), 3.84 (dd, J =
9.9 Hz, J = 8.9 Hz, 1H), 3.79 (dd, J = 7.6 Hz, J = 10.9 Hz, 1H), 3.73 (dd, J =
2.1 Hz, J = 10.9 Hz, 1H), 3.58 (dd, J = 10.8 Hz, J = 8.9 Hz, 1H), 3.31 (dd, J =
2.6 Hz, J = 10.8 Hz, 1H), 1.06 (s, 9H), 0.97 (s, 9H); 13C NMR (50 MHz, CDCl3):
δ 163.4, 160.0, 137.6, 137.5, 137.3, 129.2, 128.9, 128.6, 128.4, 127.9, 97.6, 96.5,
78.5, 76.2, 75.9, 75.3, 75.0, 73.7, 73.4, 67.8, 67.6, 65.0, 42.7, 27.4, 26.8, 23.2,
20.8.
1,3-Disaccharide 28
To a stirred solution of 26 (53 mg, 0.071 mmol) in dry DMF (6.8 mL),
TBAF (22 mg, 0.071 mmol) was added at rt. The mixture was stirred for 1.5
h; then it was diluted with CH2Cl2 (40 mL) and washed with a saturated
solution of NH4Cl (1 × 20 mL). The organic phase was dried over Na2SO4
and evaporated under reduced pressure. The crude was purified by flash col-
umn chromatography on silica gel (petroleum ether:ethyl acetate = 2:3, Rf =
0.3) to afford 28 (28 mg, 71%) as a white solid. [α]2D5 = +141 (c 0.5, CHCl3);
m.p. = decomposition (172–175◦C); Anal. Calcd for C33H34O9S: C, 65.33; H,
1
5.65. Found: C, 65.54; H, 5.42. H NMR (400 MHz, CDCl3): δ 7.39–7.28 (m,
13H), 7.19–7.16 (m, 2H), 5.69 (d, J = 2.8 Hz, 1H), 4.91–4.88 (A part of an
AB system, JA−B = 10.4 Hz, 1H), 4.87–4.84 (A part of an AB system, JA−B
=
10.8 Hz, 1H), 4.84–4.82 (B part of an AB system, JB−A = 10.4 Hz, 1H), 4.62–
4.59 (A part of an AB system, JA−B = 12.4 Hz, 1H), 4.61 (d, J = 9.6 Hz, 1H),
4.57–4.54 (B part of an AB system, JB−A = 10.8 Hz, 1H), 4.56–4.53 (B part of
an AB system, JB−A = 12.4 Hz, 1H), 4.10 (ddd, J = 9.6 Hz, J = 3.2 Hz, J =
3.6 Hz, 1H), 4.05–4.01 (m, 1H), 3.93 (dd, J = 12.4 Hz, J = 3.2 Hz, 1H), 3.86
(dd, J = 12.4 Hz, J = 3.6 Hz, 1H), 3.77–3.65 (m, 4H), 3.27 (dd, J = 2.8 Hz,
J = 10.8 Hz, 1H), 3.22 (bs, 1H), 2.31 (bs, 1H), 1.70 (bs, 1H); 13C NMR (50
MHz, CDCl3): δ 162.7, 159.8, 137.4, 137.3, 128.8, 128.6, 128.5, 128.4, 128.1,
128.0, 127.9, 96.8, 94.7, 80.4, 78.6, 76.1, 75.8, 75.4, 73.6, 73.5, 68.1, 63.2, 60.7,
42.6.

G. Gabrielli et al.
138
Cycloadduct 30
To a mixture of dry DMSO (0.68 mL, 9.6 mmol) and dry CH2Cl2 (2.3
mL), cooled to –78◦C, trifluoroacetic anhydride (0.39 mL, 2.74 mmol) was
added dropwise under vigorous stirring. The suspension obtained was warmed
to –60◦C and a solution of 34 (150 mg, 0.457 mmol) in dry CH2Cl2 (5 mL)
was added. The mixture was stirred for 1 h at –60◦C, and then Et3N (0.79
mL, 5.484 mmol) was added and the temperature was allowed to warm to –
30◦C. After 1.5 h the mixture was diluted with CH2Cl2 (30 mL) and washed
with a saturated solution of NH4Cl (2 × 10 mL). The organic phase was
dried over Na2SO4 and evaporated under reduced pressure to a complex re-
action mixture that was diluted with CHCl3(6 mL) and treated with solid
PhtNSCl (100 mg, 0.457 mmol). The mixture was stirred at rt for 15 min,
and then 3,4,6-tri-O-benzyl-D-glucal (190 mg, 0.457 mmol) and Py (0.36 mL,
4.11 mmol) were added and the mixture was heated to 60◦C. After 18 h, Ph-
tNSCl (100 mg, 0.457 mmol) was added and the mixture was stirred for 24
h at 60◦C. PhtNSCl (100 mg, 0.457 mmol) was then added and the mixture
was stirred for additional 12 h. The mixture was then diluted with CHCl3(40
mL) and washed with a saturated solution of NH4Cl (2 × 10 mL). The organic
phase was dried over Na2SO4 and evaporated under reduced pressure. The
crude was purified by flash column chromatography on silica gel (petroleum
ether:ethyl acetate = 3:2, Rf = 0.5) to afford 30 (55 mg, 17%) as a yellow
solid. [α]2D3 = +1 (c 0.26, CHCl3); m.p. = 183–185◦C; ESI MS: 773.8 ([MH]+),
1
795.4 ([M+Na]+), 811.3[M+K]+); H NMR (400 MHz, C6D6): δ 7.65–7.62 (m,
2H), 7.33–7.31 (m, 1H), 7.26–7.24 (m, 2H), 7.14–7.02 (m, 13H), 6.93–6.88 (m,
2H), 5.23 (d, J = 2.8 Hz, 1H), 4.85–4.83 (A part of an AB system, JA−B = 10.8
Hz, 1H), 4.82–4.79 (A part of an AB system, JA−B = 11.2 Hz, 1H), 4.77–4.74
(B part of an AB system, JB−A = 10.8 Hz, 1H), 4.74–4.72 (m, 1H), 4.62–4.59
(B part of an AB system, JB−A = 11.2 Hz, 1H), 4.35–4.32 (A part of an AB
system, JA−B = 12.0 Hz, 1H), 4.27–4.24 (B part of an AB system, J = 12.0
Hz, 1H), 3.99–3.96 (m, 1H), 3.85–3.80 (m, 1H), 3.68 (dd, J = 2.8 Hz, J =
11.2 Hz, 1H), 3.65 (dd, J = 10.8 Hz, J = 1.6 Hz, 1H), 3.59 (dd, J = 5.6 Hz,
J = 11.2 Hz, 1H), 3.55–3.51 (m,1H), 3.50–3.45 (m, 1H), 3.29–3.27 (m, 1H),
3.11–3.03 (m, 3H), 2.64 (dd, J = 2.8 Hz, J = 10.8 Hz, 1H); 13C NMR (50
MHz, C6D6): δ 160.5, 156.3, 140.3, 138.1, 137.6, 132.9, 128.7, 128.4, 128.2,
97.4, 96.7, 96.2, 78.9, 75.4, 75.1, 74.9, 73.7, 73.3, 72.9, 70.1, 68.0, 66.8, 59.4,
42.7.
N-Benzenesulfonyl β-oxy-imino-δ-lactone 31
To a stirred solution of hydroxylamine hydrochloride (278 mg, 2.96 mmol)
in H2O (6 mL), sodium acetate (402 mg, 2.96 mmol) was added. The mixture
was stirred for 30 min and then was added to a solution of 3 (R = Piv, 99 mg,
0.296 mmol) in i-PrOH (3.7 mL). The reaction mixture was stirred at rt for

Stereoselective Synthesis of 1,3-Disaccharides
139
12 h, then diluted with EtOAc (50 mL) and washed with H2O (3 × 10 mL).
The organic phase was dried over Na2SO4 and evaporated under reduced pres-
sure to afford the crude product as yellow oil. To a stirred solution of crude
oxime in dry CH2Cl2 (5 mL), cooled to 0◦C, Et3N (62 µL, 0.443 mmol), ben-
zenesulfonyl chloride (57 µL, 0.443 mmol) and a catalytic amount of DMAP
were added. The mixture was stirred for 1 h, diluted with CH2Cl2 (50 mL), and
washed with brine (3 × 10 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure and the crude was purified by flash column
chromatography on silica gel (petroleum ether:ethyl acetate = 1:2, 0.1% Et3N,
Rf = 0.4) to afford 31 (25.5 mg, 18%) as a yellow oil. ESI MS: 490.3 ([M+H]+),
1
512.3 ([M+Na]+), 528.2 [M+K]+); Selected data: H NMR (200 MHz, CDCl3):
δ 8.12–7.94 (m), 7.81–7.52 (m), 7.40–7.15 (m), 6.02 (s), 3.64 (s), 3.56–3.48 (A
part of an AB system, JA−B = 19.5 Hz), 3.36–3.28 (B part of an AB system,
JB−A = 19.5 Hz). A sample of the unprotected oxime was purified by flash
column chromatography on silica gel (petroleum ether:ethyl acetate = 1:10,
Rf = 0.4) for characterization. 1H NMR (400 MHz, CDCl3): δ 7.45–7.26 (m,
5H), 4.66–4.63 (A part of an AB system, JA−B = 11.6 Hz, 1H), 4.53–4.50 (B
part of an AB system, JB−A = 11.6 Hz, 1H), 4.27 (d, J = 3.2 Hz, 1H), 4.22
(dd, J = 11.6 Hz, J = 6.4 Hz, 1H), 4.09 (dd, J = 11.6 Hz, J = 5.2 Hz, 1H),
3.96–3.92 (m, 1H), 3.69–3.63 (A part of an AB system, JA−B = 24.4 Hz, 1H),
3.39–3.33 (B part of an AB system, JB−A = 24.4 Hz,1H), 1.15 (s, 9H); 13C NMR
(50 MHz, CDCl3): δ 178.3, 174.5, 165.7, 135.7, 128.7, 128.5, 74.4, 72.5, 71.2,
64.2, 38.8, 34.2, 27.0. Since the formation of degradation side products was
observed during purification, the unprotected oxime was used without any fur-
ther purification.
4,6-O-(2-Phenylsulfonyl)ethylidene-2-deoxy-D-glucopyranose
(33)
To a solution of 17 (2.87 g, 9.18 mmol) in 1,4-dioxane (90 mL), cooled to 0◦C,
HCl 8N (23 mL) was gently added. The solution was then warmed to rt, stirred
for 1.5 h, diluted with CH2Cl2 (100 mL), and washed with a saturated solu-
tion of NaHCO3 (2 × 20 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The crude was purified by flash column
chromatography on silica gel (petroleum ether:ethyl acetate:CH2Cl2 = 1:3:0.3,
Rf = 0.3) to afford 33 (2.36 g, 78%) as a white solid. m.p.= 155–157◦C; Anal.
Calcd for C14H18O7S: C, 50.90; H, 5.49. Found: C, 51.32; H, 5.60. 1H NMR (250
MHz, CDCl3): δ 8.03–7.48 (m, 4H), 7.80–7.45 (m, 6H), 5.29 (bd, J1−2 = 3.8 Hz,
1H), 5.06–5.01 (m, 2H), 4.85 (bd, J1−2 = 9.5 Hz, 1H), 4.20–3.85 (m, 4H), 3.83–
3.30 (m, 8H), 3.23–3.00 (m, 4H), 2.40–2.10 (m, 3H), 2.20 (bs, 1H), 1.78–1.50 (m,
2H); 13C NMR (50 MHz, CDCl3): δ 139.7, 134.0, 133.9, 129.1, 128.2, 96.8, 94.5,
92.5, 83.6, 82.6, 68.6, 68.3, 67.7, 65.8, 65.0, 62.1, 59.8, 39.9, 37.2.

G. Gabrielli et al.
140
2-Deoxy-4,6-O-(2-phenylsulfonyl)ethylidene-D-arabino-1,
5-hexonolactone (34)
To a suspension of 33 (300 mg, 0.9 mmol) in dry benzene (19 mL), freshly
prepared Fetizon reagent (2.53 g, 4.5 mmol) was added and the mixture was
heated to 80◦C. The mixture was refluxed for 10 h, then cooled to rt, diluted
with CH2Cl2 (30 mL), and filtered through a pad of Celite. The filtrate was
evaporated under reduced pressure to dryness and the crude was purified
by flash column chromatography on silica gel (petroleum ether:ethyl acetate
= 1:4, Rf = 0.4) to afford 34 (171 mg, 58%) as a white solid. [α]2D5 = +41 (c
1.06, CHCl3); m.p. = 128–130◦C; Anal. Calcd for C14H16O7S: C, 51.21; H, 4.91.
Found: C, 50.83; H, 4.87. 1H NMR (400 MHz, CDCl3): δ 7.96–7.93 (m, 2H), 7.73–
7.69 (m, 1H), 7.64–7.29 (m, 2H), 5.13–5.11 (X part of an ABX system, JX−A
=
5.6 Hz, JX−B = 4.4 Hz, 1H), 4.23 (dd, J6a−5 = 5.2 Hz, J6a−6b = 10.4 Hz, 1H), 4.06
(m, 1H), 3.91 (ddd, J5−6a = 5.2 Hz, J5−6b = 10.4 Hz, J5−4 = 10.0 Hz, 1H), 3.62
(dd, J6b−5
=
J6b−6a = 10.4 Hz, 1H), 3.59–3.48 (m, 3H), 3.19–3.13 (A part of an
ABX system, JA−B = 18.4 Hz, JA−X = 8.4 Hz, 1H), 2.67–2.61 (B part of an ABX
system, JB−A = 18.4 Hz, JB−X = 7.2 Hz, 1H, H2b); 13C NMR (50 MHz, CDCl3): δ
167.8, 139.5, 134.2, 129.3, 128.2, 96.9, 80.3, 67.7, 67.2, 66.0, 59.5, 37.4.
ACKNOWLEDGEMENT
The authors thank Mrs. Brunella Innocenti for technical support. This work
was financially supported by the University of Florence and MIUR (Rome)
within the project PRIN 2006.
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