Synthetic oligorhamnans related to the most common O-chain backbone from phytopathogenic bacteria

Article abstract of DOI:10.1016/j.tet.2006.06.084

The synthesis of the tetrasaccharide rhamnanic motif α-l-Rha-(1→3)-α-l-Rha-(1→2)-α-l-Rha-(1→ 2)-α-l-Rha and its dimerization to octasaccharide have been developed. Three different pathways toward the dimerization have been investigated; the best one was b

Full text of DOI:10.1016/j.tet.2006.06.084

Tetrahedron 62 (2006) 8474–8483
Synthetic oligorhamnans related to the most common O-chain
backbone from phytopathogenic bacteria
*
Emiliano Bedini, Antonella Carabellese, Daniela Comegna, Cristina De Castro
and Michelangelo Parrilli
Dipartimento di Chimica Organica e Biochimica, Universitaꢀ di Napoli ‘Federico II’, Complesso Universitario Monte Santangelo,
Via Cintia 4, 80126 Napoli, Italy
Received 31 March 2006; revised 5 June 2006; accepted 22 June 2006
Available online 14 July 2006
Abstract—The synthesis of the tetrasaccharide rhamnanic motif a-L-Rha-(1/3)-a-L-Rha-(1/2)-a-L-Rha-(1/2)-a-L-Rha and its di-
merization to octasaccharide have been developed. Three different pathways toward the dimerization have been investigated; the best one
was based on a [4+2]+2 stepwise condensation of a rhamnose tetrasaccharide with two rhamnosyl N-phenyl trifluoroacetimidates as glycosyl
donors and on an orthogonal set of protecting groups consisting of benzoyl, levulinoyl, and allyl groups.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
3)-α-L-Rha-(1 3)-α-L-Rha-(1 2)-α-L-Rha(1
n
A
The mechanism of pathogenic agent recognition by plants is
still unknown, even if many efforts toward understanding are
currently underway.1 It has been recently suggested that the
3)-α-L-Rha-(1 3)-α-L-Rha-(1 2)-α-L-Rha(1 2)-α-L-Rha(1
recognition is analogous to the innate immunity system of
animals,2 which is based on the perception of pathogen-asso-
ciated molecular patterns (PAMPs), characteristic structures
of the pathogen indispensable for its growth within the host.3
Since lipopolysaccharides (LPS) cover almost 80% of the
cell surface, they are one of a group of general elicitors
that can be recognized by plants to trigger a defense re-
sponse; this role is induced especially by lipid-A and core4
that are the most highly conserved regions of LPS in differ-
ent Gram negative bacteria.5 A recent study showed that
some synthetic oligorhamnans are also able to trigger de-
fense responses in plants and therefore they are PAMP.6
The oligosaccharides used in that work were the rhamnose
trisaccharide A and its dimer and trimer; they were chosen
as first compounds for phytopathogenic tests, since A repre-
sents the motif of the most general backbone of the LPS
O-antigenic region (O-chain) from phytopathogenic bacte-
ria. Nevertheless, only a few bacterial strains present A as
a repeating unit of their O-chain backbone; the most com-
mon O-chain backbones are characterized by motifs such as
B or C that differ from A by the addition of a 3-linked- or
2-linked-rhamnose unit (Fig. 1).7 So far, tetrasaccharide
B
n
3)-α-L-Rha-(1 3)-α-L-Rha-(1 2)-α-L-Rha(1 3)-α-L-Rha(1
n
C
Figure 1. Common rhamnanic backbones of O-antigen polysaccharides
from phytopathogenic bacteria.
motif B has been most frequently found in the O-chains of
LPS from phytopathogenic bacteria. In this paper, the syn-
thesis of B and its oligomerization is described; the synthetic
oligorhamnans obtained will be the object of molecular
mechanics calculations and phytopathogenic tests, in order
to compare their 3D-structures and their eventual biological
activities with the oligorhamnans related to motif A.
2. Results and discussion
The synthesis of a-linked oligorhamnans was the target of
several reports in the last two decades;8 recently, a methyl
and an octyl glycoside bearing a tetrasaccharide correspond-
ing to motif B were also synthesized,9 nevertheless
their oligomerization was not attempted. The synthetic
approach described in this paper aimed at the synthesis
Keywords: Rhamnose; Glycosylation; Oligosaccharide; Lipopolysaccha-
ride; Phytopathogenic bacteria.
* Corresponding author. Tel.: +39 81 674146; fax: +39 81 674393; e-mail:
ebedini@unina.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.084

E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
8475
of a tetrasaccharide building-block that would be easily
functionalized both as a glycosyl donor and a glycosyl
acceptor, thus permitting stepwise condensation to higher
oligosaccharides. Therefore, the protection pattern of this
tetrasaccharide should have two orthogonal temporary pro-
tecting groups at positions O-1A and O-3D and a permanent
protecting group at the other positions; an allyl group was
chosen for the anomeric position, a chloroacetyl for position
O-3D, and benzoyls for the other positions. Tetrasaccharide 1
with this protection pattern was obtained by condensing tri-
saccharide donor 210 with acceptor 311 in CH2Cl2 at ꢀ50 ꢁC
with BF3$OEt2 as activator (72% yield) (Scheme 1). The
a-configuration of the newly formed glycosidic linkage was
ascertained by the heteronuclear C1–H1 coupling constant of
172 Hz measured in a J-coupled HSQC experiment. Selec-
tive removal of the chloroacetyl moiety was easily achieved
by treating an aliquot of 1 with thiourea; the tetrasaccharide
acceptor 4 was obtained in 71% yield. Another aliquot of 1
was de-O-allylated with PdCl2 in 1:1 CH2Cl2/MeOH to
obtain a tetrasaccharide glycosyl donor, the resulting hemi-
acetal 5 (80%) was subsequently activated by treatment with
Cl3CCN and DBU to give the trichloroacetimidate 6 in 61%
yield. Unfortunately, the glycosylation of 6 with 4 was un-
successful; octasaccharide 7 was obtained in very low yield
(<15%) by activating 6 with BF3$OEt2 at ꢀ50 ꢁC. No better
yield was observed even by changing several reaction condi-
tions. Interestingly, the glycosylation of trisaccharide tri-
chloroacetimidate 2, that is related to 6, with rhamnose
oligosaccharides had been already successfully accom-
plished.10 Thus, we hypothesized that the upper limit for
such couplings between rhamnose oligosaccharides was
the use of a trisaccharide donor and a new strategy for the
dimerization of 1 was planned. This new approach was to
dimerize 1 by stepwise condensation of tetrasaccharide
acceptor 4 with two different disaccharide donors that would
have a temporary protecting group at positions O-2B and
O-3B, respectively. In analogy to the [4+4] strategy, a chloro-
acetylwas chosenas temporaryprotectinggroup;compounds
8 and 9 was therefore, designed as suitable disaccharide
donors (Scheme 2).
The synthesis of compound 8 was started by treating the
known diol 1012 with BzCl in 2:1 CH2Cl2/Py at ꢀ30 ꢁC to
give selectively 3,4-di-O-benzoylated alcohol 11 in 88%
NH
OR
O
CCl3
O
A
R'O
O
BzO
R'O
O
BzO
O
OAll
O B
R'O
O
O
a
+
R'O
BzO
BzO
O
O
BzO
OBz
OH
3
O
C
O
R'O
BzO
O
ClAcO
OR'
OBz
1: R= All; R'= Bz; R''= ClAc
4: R= All; R'= Bz; R''= H
2
O
D
b
d
c
R'O
e
5: R= H; R'= Bz; R''= ClAc
R''O
OR'
6: R= C(NH)CCl3; R'= Bz; R''= ClAc
29: R= All; R'=R''= H
BzO
BzO
OAll
BzO
O
a
4 + 6
BzO
BzO
BzO
BzO
O
O
BzO
BzO
O
O
O
O
O
O
BzO
BzO
BzO
O
O
BzO
BzO
ClAcO
O
O
O
O
7
BzO
BzO
ꢁ
˚
Scheme 1. Reagents and conditions: (a) BF3$OEt2, AW-300 4 A MS, CH2Cl2, ꢀ50 C, to 1: 75 min, 72%; to 7: 2 h, <15%; (b) NH2CSNH2, 1:1 EtOH/DMF, rt,
2 days, 71%; (c) PdCl2, 1:1 CH2Cl2/MeOH, rt, 2 days, 80%; (d) Cl3CCN, DBU, 0 ꢁC, 3 h, 61%; (e) NaOMe, MeOH, 40 ꢁC, overnight, 78%.

8476
E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
BzO
BzO
BzO
BzO
RO
BzO
BzO
BzO
BzO
O
BzO
O
BzO
O
BzO
O
OAll
O
BzO
O
O
O
O
O
O
O
O
BzO
O
O
BzO
BzO
BzO
BzO
O
BzO
OR
BzO
BzO
BzO
BzO
BzO
HO
BzO
BzO
O
O
BzO
O
O
O
8: R=C(NH)CCl3; R'=ClAc
19: R=C(NPh)CF3; R'=Lev
OAll
O
R'O
O
O
BzO
BzO
O
BzO
BzO
O
OR
4
O
O
R'O
BzO
9: R=C(NH)CCl3; R'=ClAc
23: R=C(NPh)CF3; R'=Lev
BzO
Scheme 2. [4+2]+2 Strategy for the dimerization of the rhamnanic motif B.
yield (Scheme 3). Compound 11 was chloroacetylated (56%)
and the resulting fully-protected thioglycoside 12 was
coupled with 3 by activation with NIS/TfOH at ꢀ30 ꢁC.
Disaccharide 13 was obtained in unsatisfactory yield
(45%); this result was consistent with a recent report on
the poor outcome of a condensation reaction involving a
2-chloroacetylated trichloroacetimidate as rhamnosyl donor.13
In spite of the limited yield of the coupling, compound 13 was
de-O-allylated with PdCl2 to give hemi-acetal 14 (53%)
that was converted in turn to trichloroacetimidate 8 (80%).
Condensation of 8 with tetrasaccharide acceptor 4 at ꢀ50 ꢁC
with BF3$OEt2 as activator gave hexasaccharide 15 in moder-
ate yield (48%).
chromatography, the resulting hexasaccharide was contami-
nated by traces of tetrasaccharide 20, a side product due to
self-condensation of 19. Treatment with hydrazinium acetate
in 7:1 CH2Cl2/MeOH cleaved the Lev group and reduced
the allyl aglycon to propyl by the diimide generated in situ,17
affording pure hexasaccharide acceptor 21 in 77% yield
(calculated from 3). A J-coupled HSQC experiment on 21
confirmed the a-configuration of the newly formed glyco-
sidic linkage (1JC,H¼172 Hz). The global yield of the syn-
thetic path from 10 to 21 was much better with Lev than
ClAc as O-2 temporary protecting group (30% vs 5%).
This result prompted us to re-design also the second di-
saccharide donor with a Lev temporary group. Thus, the syn-
thesis of donor 22 (to replace 9) was undertaken. Diol 10 was
regioselectively 2-O-benzoylated via ortho-ester as already
reported13 and the resulting alcohol 23 was converted to
3-O-levulinoylated thioglycoside 24 (89%). Coupling of 24
with acceptor 2518 proceeded in high yield (87%) by activa-
tion of 24 with NIS/TfOH at ꢀ30 ꢁC. Disaccharide 26 was
de-O-allylated (60%) and the resulting hemi-acetal 27 was
converted into N-phenyltrifluoroacetimidate 22 (58%). Elon-
gation of hexasaccharide 21 by condensation with disaccha-
ride donor 22 gave, after column chromatography, an
octasaccharide contaminated by tetrasaccharide 20. Benzoyl
The low global yield of the synthetic path from diol 10 to
hexasaccharide 15 (5%) necessitated the re-designing of
this synthetic path. The chloroacetyl temporary protecting
group was replaced with a levulinoyl group; in addition
the trichloroacetimidate leaving group on the disaccharide
donor was replaced by a N-phenyltrifluoroacetimidate,14
because the latter was recently shown to be very effective in
glycosylation reactions involving deoxysugars (Scheme 2).15
Thus, alcohol 11 was treated with levulinic acid (LevOH) in
the presence of N,N0-diisopropylcarbodiimide (DIPC) and
DMAP to give the 2-O-levulinoylated thioglycoside 16
(91%) that was coupled with 3 by activation with NIS/
TfOH at ꢀ30 ꢁC to afford disaccharide 17 in 83% yield.
Hemi-acetal 18 was obtained from 17 with PdCl2 (83%)
and then converted into N-phenyltrifluoroacetimidate 19
(72%) by treatment with CF3C(NPh)Cl and NaH (Scheme
3).16 Coupling of disaccharide donor 19 with tetrasaccharide
acceptor 4 by activation with TMSOTf in CH2Cl2 at 0 ꢁC
proceeded very satisfyingly. Actually, an exact yield of
this condensation was not obtained, since, after column
ꢁ
and levulinoyl deprotection by Zemplen transesterification
of the mixture afforded pure propyl octasaccharide 28
(49% calculated from 21) after size exclusion chromato-
graphy, the 1H NMR spectrum of which is reported in
Figure 2. Similarly, ester deprotection of 1 and 15 gave tetra-
saccharide 29 (78%) and hexasaccharide 30 (90%) (Schemes
1 and 3). Compounds 28, 29, and 30 are currently the object
of molecular mechanics calculations and phytopathogenic
tests.

R'O
R'O
BzO
SEt
R'O
R'O
R'O
R'O
O
O
BzO
R'O
R'O
R'O
OR
OR
A
O
R'O
BzO
BzO
BzO
O
O
O
O
B
E
R'O
O
O
O
O
O
OR
10: R= R'= H
O
D
F
O
O
C
a
R'O
R''O
4 (0.4 eq.), j
R'O
11: R= H; R'= Bz
12: R= ClAc; R'= Bz
16: R= Lev; R'= Bz
23: R= Bz; R'= H
24: R= Bz; R'= Lev
3 (0.75 eq.), e
R'O
b
13: R= α-All; R'= ClAc
15: R= All, R'= Bz, R''= ClAc
30: R= All, R'=R''= H
c
f
l
d
14: R= H; R'= ClAc
g
8: R= α-C(NH)CCl3; R'= ClAc
17: R= α-All; R'= Lev
18: R= H; R'= Lev
3 (0.75 eq.), e
4 (0.25 eq.), k
c
21: R= Pr, R'= Bz, R''= H
f
h
BzO
BzO
OBz
19: R= C(NPh)CF3; R'= Lev
OLev
OAll
BzO
O
O
O
O
O
O
O
OBz
O
e
BzO
LevO
BzO
OBz
OBz
20
HO
OBz
25 (0.75 eq.)
HO
HO
BzO
HO
HO
HO
HO
HO
HO
HO
HO
BzO
LevO
HO
O
O
O
HO
O
A
HO
OR
OPr
21 (0.25 eq.), m
O
HO
O
E
O
B
O
O
O
O
H
O
F
O
O
D
O
G
O
BzO
O
C
O
HO
BzO
HO
HO
26: R= α-All
28
f
27: R= H
22: R= C(NPh)CF3
h
Scheme 3. Reagents and conditions: (a) BzCl, 2:1 CH2Cl2/Py, ꢀ30 ꢁC, 2.5 h, 88%; (b) ClCH2COCl, 1:1 Py/DMF, rt, 4 h, 56%; (c) LevOH, DIPC, DMAP, rt, to 16: 1 h, 91%; to 24: 30 min, 89%; (d) see Ref. 12; (e) NIS,
ꢁ
ꢁ
˚
TfOH, AW-300 4 A MS, CH2Cl2, ꢀ30 C, to 13: 90 min, 45%; to 17: 90 min, 83%; to 26: 3 h, 87%; (f) PdCl2, 3:1 CH2Cl2/MeOH, rt, overnight, to 14: 53%; to 18: 83%; to 27: 60%; (g) Cl3CCN, DBU, CH2Cl2, 0 C, 2 h,
ꢁ
ꢁ
˚
˚
˚
80% (a/b¼6:1); (h) CF3C(NPh)Cl, NaH, 4 A MS, CH2Cl2, 0 C to rt, 4 h, to 19: 72% (a/b¼1:1); to 22: 58% (a/b¼1:1); (j) BF3$OEt2, AW-300 4 A MS, CH2Cl2, ꢀ50 C, 4 h, 48%; (k) (i) TMSOTf, AW-300 4 A MS,
ꢁ
ꢁ
ꢁ
˚
CH2Cl2, 0 C, 3 h; (ii) N2H4, AcOH, 7:1 CH2Cl2/MeOH, rt, 2 h, 77% over two steps; (l) NaOMe, 3:1 MeOH/CH2Cl2, 40 C, overnight, 77%; (m) (i) TMSOTf, AW-300 4 A MS, CH2Cl2, 0 C, overnight, (ii) NaOMe, 3:1
MeOH/CH2Cl2, 40 ꢁC, 2 days, 49% over two steps.

8478
E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
Figure 2. 1H NMR spectrum (D2O, 400 MHz; acetone as internal standard) of the octasaccharide 28.
3. Experimental
3.1. General methods
where differently specified. Gel-filtration chromatographies
were performed on a Sephadex G-10 column (2.0ꢂ90 cm)
with water as eluant.
1H and 13C NMR spectra were recorded on Varian XL-200
(1H: 200 MHz; 13C: 50 MHz), Varian Gemini-300 (1H:
300 MHz; 13C: 75 MHz) or Bruker DRX-400 (1H:
400 MHz; 13C: 100 MHz) instruments in CDCl3 (CHCl3 as
internal standard, 1H: CHCl3 at d 7.26; 13C: CDCl3 at
d 77.0) and in D2O (acetone as internal standard, 1H:
(CH3)2CO at d 2.22; 13C: (CH3)2CO at d 31.5). Assignment
of proton and carbon chemical shifts of the deprotected
oligosaccharides was based on 2D NMR experiments such
as COSY, TOCSY, NOESY, and HSQC. Heteronuclear
C1–H1 coupling constants were measured with J-coupled
HSQC experiments. Positive ESI-MS spectra were recorded
on a Finnigan LCQ-DECA ion trap mass spectrometer. Pos-
itive MALDI-MS spectra were recorded on an Applied Bio-
system Voyager DE-PRO MALDI-TOF mass spectrometer
in the positive mode; compounds were dissolved in the
appropriate solvent at a concentration of 1 mg/mL and 1 mL
of these solutions were mixed with 1 mL of a 20 mg/mL so-
lution of 2,5-dihydroxybenzoic acid in 7:3 CH3CN/0.1 M
aqueous TFA. IR spectra were recorded on a JASCO-
FTIR-430 spectrometer. Optical rotations were measured
on a JASCO P-1010 polarimeter. Analytical thin layer chro-
matography (TLC) was performed on aluminum plates pre-
coated with Merck silica gel 60 F254 as the adsorbent. The
plates were developed with 5% H2SO4 ethanolic solution
and then heated to 130 ꢁC. Column chromatography was
performed on Merck Kieselgel 60 (63–200 mesh), except
3.1.1. Allyl (2,4-di-O-benzoyl-3-O-chloroacetyl-a-L-
rhamnopyranosyl)-(1/3)-(2,4-di-O-benzoyl-a-L-rhamno-
pyranosyl)-(1/2)-(3,4-di-O-benzoyl-a-L-rhamnopyrano-
syl)-(1/2)-3,4-di-O-benzoyl-a-L-rhamnopyranoside (1).
A mixture of 3 (179 mg, 0.43 mmol) and 2 (734 mg,
0.56 mmol) was coevaporated three times with toluene, the
residue was dried, and then mixed with freshly activated
˚
AW-300 4 A molecular sieves, suspended under argon in
CH2Cl2 (15 mL), and stirred at ꢀ50 ꢁC. BF3$OEt2 (35 mL,
0.28 mmol) was then added. After 75 min the reaction mix-
ture was quenched with some drops of Et3N. After filtration
over a Celite pad, the mixture was concentrated to give a resi-
due that after column chromatography (5:1 to 3:1 petroleum
ether/ethyl acetate) afforded 1 (480 mg, 72%) as a white
foam. [a]D +95.8 (c 1.0, CH2Cl2). IR (thin film, NaCl)
3030, 2913, 1720, 1458, 1275 cmꢀ1 1H NMR (CDCl3,
.
400 MHz) d 8.15–7.09 (m, 40H), 5.98 (m, 1H), 5.83 (dd,
J¼9.9, 3.1 Hz, 1H), 5.68–5.57 (m, 3H), 5.54 (br s, 1H),
5.43–5.27 (m, 5H), 5.18 (br s, 1H), 5.17 (br s, 1H), 5.12
(br s, 1H), 5.01 (br s, 1H), 4.80 (br s, 1H), 4.50 (dd,
J¼10.0, 3.4 Hz, 1H), 4.40 (br s, 1H), 4.36 (br s, 1H), 4.30
(dd, J¼9.7, 3.6 Hz, 1H), 4.23 (dq, J¼9.6, 6.1 Hz, 1H),
4.13 (m, 3H), 4.00 (dq, J¼10.0, 6.1 Hz, 1H), 3.72 (AB d,
J¼14.9 Hz, 1H), 3.68 (AB d, J¼14.9 Hz, 1H), 1.41 (d,
J¼6.1 Hz, 3H), 1.35 (d, J¼6.1 Hz, 3H), 1.20 (d, J¼6.1 Hz,
3H), 1.01 (d, J¼6.1 Hz, 3H); 13C NMR (CDCl3, 50 MHz)
d 165.8–165.3 (CO), 133.8–133.3 (Cipso, OCH2CH]CH2),

E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
8479
129.8–128.3 (C-Ar), 118.1 (OCH2CH]CH2), 100.8, 99.3,
99.0, 97.9 (CA1 , CB1 , C1C, C1D), 78.0, 77.5, 75.1 (CA2 , C2B, CC3 ),
72.8, 71.8, 71.7, 71.6, 71.5, 71.3, 70.6, 70.5, 70.3, 68.1,
67.5, 67.4, 67.3, 66.9 (CC2 , CD2 , C3A, C3B, C3D, CA4 , C4B, CC4 ,
CD4 , CA5 , CB5 , CC5 , C5D, OCH2CH]CH2), 40.3 (CH2Cl),
17.6–17.2 (CA6 , CB6 , C6C, C6D). MALDI-MS for C85H79ClO26
(m/z): Mr (calcd) 1550.45; Mr (found) 1573.27 (M+Na)+.
Anal. Calcd: C 65.78, H 5.13. Found: C 65.97, H 5.10.
(br s, 1H), 5.42 (m, 2H), 5.31 (t, J¼9.5 Hz, 1H), 5.19 (br s,
2H), 5.17 (br s, 1H), 4.88 (br s, 1H), 4.63 (br s, 1H), 4.51
(dd, J¼9.5, 3.3 Hz, 1H), 4.40 (br s, 1H), 4.33 (m, 2H), 4.13
(dq, J¼9.5, 6.1 Hz, 1H), 4.01 (dq, J¼9.5, 6.1 Hz, 1H), 3.72
(AB d, J¼14.9 Hz, 1H), 3.68 (AB d, J¼14.9 Hz, 1H), 1.43
(d, J¼6.1 Hz, 3H), 1.39 (d, J¼6.1 Hz, 3H), 1.30 (d,
J¼6.1 Hz, 3H), 0.93 (d, J¼6.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 166.0–165.4 (CO), 161.4 (Cl3CC]NH),
133.8–133.4 (Cipso), 130.0–128.3 (C-Ar), 100.9, 100.2,
100.1, 97.2 (CA1 , C1B, C1C, C1D), 78.1, 75.1, 74.9, 72.9–71.1,
70.5, 70.2, 69.8, 69.7, 67.7–67.5 (CA2 , CB2 , CC2 , CD2 , C3A, C3B,
CC3 , CD3 , CA4 , C4B, C4C, C4D, C5A, C5B, CC5 , CD5 ), 40.3 (CH2Cl),
17.7–17.3 (CA6 , C6B, C6C, CD6 ). Anal. Calcd: C 60.91, H 4.56,
N 0.85. Found: C 61.09, H 4.45, N 0.88.
3.1.2. Allyl (2,4-di-O-benzoyl-a-L-rhamnopyranosyl)-
(1/3)-(2,4-di-O-benzoyl-a-L-rhamnopyranosyl)-(1/
2)-(3,4-di-O-benzoyl-a-L-rhamnopyranosyl)-(1/2)-3,4-
di-O-benzoyl-a-L-rhamnopyranoside (4). A solution of 1
(189 mg, 0.12 mmol) was dissolved in 1:1 EtOH/DMF
(12 mL) and then thiourea was added (93 mg, 1.29 mmol).
After 2 days stirring at rt, the solution was diluted with
CH2Cl2, washed with 1 M HCl, 1 M NaHCO3, and water.
The organic layer was collected, dried, and concentrated to
give a residue that, after column chromatography (4:1 petro-
leum ether/ethyl acetate) afforded 4 (128 mg, 71%) as
a white foam. [a]D +116.9 (c 1.7, CH2Cl2). IR (thin film,
3.1.4. Ethyl 3,4-di-O-benzoyl-1-thio-a-L-rhamnopyrano-
side (11). A solution of 10 (2.935 g, 9.40 mmol) in 2:1
CH2Cl2/Py (12 mL) was cooled to ꢀ30 ꢁC and then treated
with a 1.1 M solution (2.25 mL) of BzCl in 2:1 CH2Cl2/Py.
After stirring for 2.5 h, the mixture was treated with some
drops of water, heated to rt, and then diluted with CH2Cl2.
The mixture was washed with water, 1 M HCl, and water
again. The organic layer was collected, dried, and concen-
trated to give a residue that, after column chromatography
(7:1 petroleum ether/ethyl acetate) afforded 11 (3.446 g,
88%) as a white foam. [a]D +8 (c 0.5, CH2Cl2). IR (thin
NaCl) 3053, 3031, 2925, 1723, 1460 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz) d 8.17–7.07 (m, 40H), 5.98 (m, 1H),
5.85 (dd, J¼9.9, 3.1 Hz, 1H), 5.64 (m, 2H), 5.58 (t,
J¼9.8 Hz, 1H), 5.53 (br s, 1H), 5.39 (m, 2H), 5.29 (d,
J¼10.8 Hz, 1H), 5.21 (br s, 1H), 5.13–5.05 (m, 4H), 5.02
(br s, 1H), 4.80 (br s, 1H), 4.48 (dd, J¼9.6, 3.1 Hz 1H),
4.41 (br s, 1H), 4.37 (br s, 1H), 4.30 (dd, J¼9.7, 3.6 Hz,
1H), 4.23 (dq, J¼9.6, 6.1 Hz, 1H), 4.13 (m, 2H), 4.03 (m,
2H), 2.17 (br s, 1H), 1.39 (d, J¼6.1 Hz, 3H), 1.34 (d,
J¼6.1 Hz, 3H), 1.16 (d, J¼6.1 Hz, 3H), 1.01 (d, J¼6.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 165.8–165.3 (CO),
133.9–133.3 (Cipso, OCH2CH]CH2), 130.0–128.2 (C-Ar),
118.1 (OCH2CH]CH2), 100.8, 99.2, 99.0, 98.3 (CA1 , C1B,
CC1 , CD1 ), 77.9, 77.0, 75.3, 75.1, 73.3–71.7, 70.6, 68.4,
68.3, 68.0, 67.4, 66.9 (CA2 , CB2 , C2C, C2D, C3A, CB3 , C3C, CD3 ,
CA4 , CB4 , CC4 , C4D, C5A, C5B, CC5 , CD5 , OCH2CH]CH2), 17.6–
17.3 (CA6 , CB6 , C6C, C6D). MALDI-MS for C63H78O25 (m/z):
Mr (calcd) 1474.48; Mr (found) 1497.42 (M+Na)+. Anal.
Calcd: C 67.56, H 5.33. Found: C 67.67, H 5.30.
1
film, NaCl) 3063, 3025, 2926, 1707, 1605 cmꢀ1. H NMR
(CDCl3, 200 MHz) d 7.99–7.30 (m, 10H), 5.62 (t,
J¼9.8 Hz, 1H), 5.53 (dd, J¼9.8, 2.6 Hz, 1H), 5.37 (br s,
1H), 4.48 (dq, J¼9.8, 6.2 Hz, 1H), 4.39 (br s, 1H), 2.71
(app oct, J¼8.4 Hz, 2H), 2.04 (br s, 1H), 1.35 (m, 6H);
13C NMR (CDCl3, 75 MHz) d 165.6 (CO), 132.9, 132.8
(Cipso), 129.4–128.0 (C-Ar), 84.1 (C1), 72.7, 71.6, 70.5,
66.7 (C2, C3, C4, C5), 24.8 (SCH2CH3), 17.1 (C6), 14.5
(SCH2CH3). ESIMS for C22H24O6S (m/z): Mr (calcd)
416.13; Mr (found) 439.33 (M+Na)+. Anal. Calcd: C
63.44, H 5.81. Found: C 63.66, H 5.88.
3.1.5. Ethyl 3,4-di-O-benzoyl-2-O-chloroacetyl-1-thio-a-
L-rhamnopyranoside (12). A solution of 11 (100 mg,
0.24 mmol) 1:1 pyridine/DMF (2.0 mL) was treated with
ClCH2COCl (86 mL, 1.08 mmol) and then stirred at rt for
4 h. The mixture was coevaporated several times with tolu-
ene, then diluted with CH2Cl2, and washed with water.
The organic layer was dried and concentrated to give a resi-
due that was subjected to column chromatography (7:1
petroleum ether/ethyl acetate) to afford 12 (66 mg, 56%)
as a yellowish oil. [a]D ꢀ17.4 (c 2.1, CH2Cl2). IR (thin
3.1.3. (2,4-Di-O-benzoyl-3-O-chloroacetyl-a-L-rhamno-
pyranosyl)-(1/3)-(2,4-di-O-benzoyl-a-L-rhamnopyra-
nosyl)-(1/2)-(3,4-di-O-benzoyl-a-L-rhamnopyranosyl)-
(1/2)-3,4-di-O-benzoyl-a-L-rhamnopyranosyl trichloro-
acetimidate (6). Compound 1 (299 mg, 0.19 mmol) was
dissolved in 1:1 MeOH/CH2Cl2 (8.0 mL), PdCl2 (8.6 mg,
95 mmol) was then added, and the mixture was vigorously
stirred at rt for 2 days, after that it was filtered over a Celite
pad, diluted with CH2Cl2, and washed with 5 M NaCl. The
organic layer was collected, dried, and concentrated to give
5 (227 mg, 80%) that was then dissolved in CH2Cl2
(15 mL) under Ar atmosphere. The solution was cooled to
0 ꢁC and then treated with Cl3CCN (76 mL, 0.76 mmol)
and DBU (6.7 mL, 45 mmol). After 3 h the solution was con-
centrated at 30 ꢁC. The residue was subjected to neutral
alumina (Brockman grade 1) column chromatography (9:2
petroleum ether/ethyl acetate) to give 6 (152 mg, 61%) as
a white foam. [a]D +101.5 (c 1.0, CH2Cl2). IR (thin film,
1
film, NaCl) 3060, 3025, 2959, 1721, 1596 cmꢀ1. H NMR
(CDCl3, 200 MHz) d 7.99–7.30 (m, 10H), 5.68–5.52 (m,
3H), 5.36 (br s, 1H), 4.50 (dq, J¼9.8, 6.2 Hz, 1H), 4.18 (s,
2H), 2.70 (m, 2H), 1.34 (m, 6H); 13C NMR (CDCl3,
50 MHz) d 166.5, 165.6, 165.3 (CO), 133.3 (2Cipso),
129.7–128.3 (C-Ar), 81.7 (C1), 73.7, 71.5, 70.0, 67.3 (C2,
C3, C4, C5), 40.6 (CH2Cl), 25.6 (SCH2CH3), 17.5 (C6),
14.9 (SCH2CH3). ESIMS for C24H25ClO7S (m/z): Mr (calcd)
492.10; Mr (found) 513.39 (M+Na)+. Anal. Calcd: C 58.47,
H 5.11. Found: C 58.77, H 5.02.
NaCl) 3023, 2970, 1741, 1650 cmꢀ1
.
1H NMR (CDCl3,
3.1.6. Allyl (3,4-di-O-benzoyl-2-O-chloroacetyl-a-L-
rhamnopyranosyl)-(1/2)-3,4-di-O-benzoyl-a-L-rhamno-
pyranoside (13). A mixture of 3 (50 mg, 0.12 mmol) and
12 (79 mg, 0.16 mmol) was coevaporated three times with
400 MHz) d 8.39 (s, 1H), 8.15–7.11 (m, 40H), 6.47 (br s,
1H), 5.84 (dd, J¼9.8, 3.2 Hz, 1H), 5.72 (t, J¼9.8 Hz, 1H),
5.68 (dd, J¼9.6, 3.2 Hz, 1H), 5.60 (t, J¼9.8 Hz, 1H), 5.55

8480
E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
toluene, the residue was dried, and then mixed with freshly ac-
˚
tivated AW-300 4 A molecular sieves and NIS (45 mg,
rhamnopyranosyl)-(1/3)-(2,4-di-O-benzoyl-a-L-
rhamnopyranosyl)-(1/3)-(2,4-di-O-benzoyl-a-L-rhamno-
pyranosyl)-(1/2)-(3,4-di-O-benzoyl-a-L-rhamnopyrano-
syl)-(1/2)-3,4-di-O-benzoyl-a-L-rhamnopyranoside (15).
A mixture of 4 (30 mg, 20 mmol) and 8 (57 mg, 60 mmol)
was coevaporated three times with toluene, the residue was
0.20 mmol). The mixture was suspended in CH2Cl2
(4.0 mL) under an Ar atmosphere and rapidly cooled
to ꢀ30 ꢁC. A 115 mg/mL solution of TfOH in CH2Cl2
(54 mL, 40 mmol) was then added. After 90 min the reaction
mixture was rapidly filtered over a Celite pad, diluted with
CH2Cl2, and washed with 10% Na2S2O3 and 1 M NaHCO3.
The organic layer was collected, dried and concentrated to
give a foamy residue. After column chromatography (7:1
petroleum ether/ethyl acetate), 13 (46 mg, 45%) was recov-
ered as a white foam. [a]D +45.1 (c 1.0, CH2Cl2). IR (thin
˚
dried, and then mixed with freshly activated AW-300 4 A mo-
lecular sieves, suspended under argon in CH2Cl2 (2.0 mL) and
stirred at ꢀ50 ꢁC. An 85 mg/mL solution of BF3$OEt2 in
CH2Cl2 (50 mL, 30 mmol) was then added. After 3 h the reac-
tion mixture was quenched with some drops of Et3N. After fil-
tration over a Celite pad, the mixture was concentrated. The
residue was subjected to column chromatography (11:1 to
6:1 toluene/ethyl acetate) to give 15 (22 mg, 48%) as a white
foam. [a]D +92 (c 0.5, CH2Cl2). IR (thin film, NaCl) 3024,
1
film, NaCl) 3055, 3026, 2948, 1726, 1600, 1255 cmꢀ1. H
NMR (CDCl3, 200 MHz) d 8.02–7.30 (m, 20H, H-Ar), 5.98
(m, 1H), 5.87 (dd, J¼10.0, 3.2 Hz, 1H), 5.80 (dd, J¼10.0,
3.2 Hz, 1H), 5.70 (dd, J¼3.2, 1.8 Hz, 1H), 5.62 (t,
J¼10.0 Hz, 1H), 5.50 (t, J¼10.0 Hz, 1H), 5.39 (d,
J¼17.0 Hz, 1H), 5.28 (d, J¼10.4 Hz, 1H), 5.00 (br s, 2H),
4.34–4.12 (m, 5H), 4.08 (AB d, J¼14.9 Hz, 1H), 3.98 (AB
d, J¼14.9 Hz, 1H), 1.39 (d, J¼6.1 Hz, 3H), 1.30 (d,
J¼6.1 Hz, 3H); 13C NMR (CDCl3, 50 MHz) d 166.0, 165.7,
165.6, 165.4, 165.1 (CO), 133.4–133.1 (Cipso, OCH2CH]
CH2), 129.8–128.4 (C-Ar), 117.9 (OCH2CH]CH2), 99.0,
97.6 (CA1 , CB1 ), 76.7, 71.7, 71.6, 71.4, 71.1, 69.3, 68.2, 67.5,
67.0 (CA2 , C2B, C3A, CB3 , CA4 , C4B, CA5 , C5B, OCH2CH]CH2),
40.5 (CH2Cl), 17.6 (CA6 , C6B). ESIMS for C45H43ClO14 (m/z):
Mr (calcd) 842.23; Mr (found) 865.49 (M+Na)+. Anal. Calcd:
C 64.09, H 5.14. Found: C 64.18, H 5.07.
2927, 2857, 1722, 1604, 1449, 1272 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz) d 8.15–7.24 (m, 60H, H-Ar), 6.00 (m,
1H), 5.85 (dd, J¼9.9, 3.1 Hz, 1H), 5.74 (dd, J¼9.9, 3.4 Hz,
1H), 5.65–5.51 (m, 4H), 5.44–5.30 (m, 7H), 5.23 (br s, 1H),
5.19 (br s, 1H), 5.14 (br s, 1H), 5.03 (br s, 1H), 4.94 (br s,
1H), 4.81 (br s, 1H), 4.71 (br s, 1H), 4.59 (br s, 1H), 4.49
(dd, J¼9.6, 3.2 Hz, 1H), 4.38–4.32 (m, 3H), 4.22–4.14 (m,
3H), 4.03–3.91 (m, 3H), 3.82 (dq, J¼9.8, 6.2 Hz, 1H), 3.73
(dq, J¼9.9, 6.2 Hz, 1H), 3.70 (AB d, J¼14.9 Hz, 1H),
3.65 (AB d, J¼14.9 Hz, 1H), 3.61 (dq, J¼9.9, 6.2 Hz, 1H),
1.42 (d, J¼6.2 Hz, 3H), 1.37 (d, J¼6.2 Hz, 3H), 1.15
(d, J¼6.2 Hz, 3H), 1.00 (d, J¼6.2 Hz, 3H), 0.85 (d,
J¼6.2 Hz, 3H), 0.79 (d, J¼6.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 165.8–165.0 (PhCO), 133.8–133.3 (Cipso
,
3.1.7. (3,4-Di-O-benzoyl-2-O-chloroacetyl-a-L-rhamno-
pyranosyl)-(1/2)-3,4-di-O-benzoyl-L-rhamnopyranosyl
trichloroacetimidate (8). Compound 13 (130 mg,
0.15 mmol) was dissolved in 3:1 CH2Cl2/MeOH (4.0 mL),
PdCl2 (5.4 mg, 60 mmol) was then added, and the mixture
was vigorously stirred overnight. It was then filtered over
a Celite pad, diluted with CH2Cl2, and washed with 5 M
NaCl. The organic layer was dried and concentrated to
give 14 (65 mg, 53%) that was then dissolved in CH2Cl2
(3.0 mL) under Ar atmosphere. The solution was cooled
to 0 ꢁC and then treated with Cl3CCN (33 mL, 0.33 mmol)
and DBU (4.3 mL, 29 mmol). After 2 h the solution was
concentrated at 30 ꢁC. The residue was subjected to neutral
alumina (Brockman grade 1) column chromatography (6:1
petroleum ether/ethyl acetate) to give 8 (61 mg, 80%; a/b¼
6:1) as a white foam. [a]D +34.5 (c 1.0, CH2Cl2). IR (thin
OCH2CH]CH2), 130.3–128.2 (C-Ar), 117.9 (OCH2CH]
CH2), 100.9, 100.8, 100.4, 99.6, 99.5, 98.9 (CA1 , C1B, C1C,
CD1 , CE1, CF1), 77.8, 76.9, 76.2, 75.4, 73.2, 73.1, 73.0, 72.2–
71.5, 70.5, 70.0, 69.9, 68.2–67.0 (CA2 , CB2 , C2C, C2D, C2E,
CF2, CA3 , CB3 , C3C, CD3 , C3E, C3F, CA4 , C4B, C4C, C4D, CE4, C4F,
CA5 , CB5, CC5 CD5 , C5E, C5F, OCH2CH2]CH2), 40.3 (CH2Cl),
17.5–17.0 (CA6 , C6B, C6C, C6D, C6E, C6F). MALDI-MS for
C125H115ClO38 (m/z): Mr (calcd) 2258.68; Mr (found)
2281.40 (M+Na)+. Anal. Calcd: C 66.41, H 5.13. Found: C
66.66, H 5.00.
3.1.9. Ethyl 3,4-di-O-benzoyl-2-O-levulinoyl-1-thio-
a-L-rhamnopyranoside (16). Compound 11 (1.541 g,
3.70 mmol) was dissolved in CH2Cl2 (15 mL) and levulinic
acid (1.89 mL, 18.5 mmol), DMAP (271 mg, 2.20 mmol),
and DIPC (2.90 mL, 18.5 mmol) were added in succession.
The mixture was stirred for 1 h at rt, then filtered over a
Celite pad, diluted with CH2Cl2, and washed with water.
The organic layer was dried and concentrated to afford a
residue that after column chromatography (4:1 petroleum
ether/ethyl acetate) gave 12 (1.735 g, 91%) as a yellowish
oil. [a]D ꢀ7 (c 0.5, CH2Cl2). IR (thin film, NaCl) 3060,
1
film, NaCl) 3048, 3020, 2970, 1738, 1655 cmꢀ1. H NMR
(CDCl3, 300 MHz) (a-anomer) d 8.76 (s, 1H), 8.02–7.33
(m, 20H, H-Ar), 6.46 (d, J¼1.8 Hz, 1H), 5.86 (dd,
J¼10.0, 3.3 Hz, 1H), 5.81 (dd, J¼10.0, 3.3 Hz, 1H), 5.73
(t, J¼10.0 Hz, 1H), 5.70 (dd, J¼3.3, 1.5 Hz, 1H), 5.53 (t,
J¼10.0 Hz, 1H), 5.07 (d, J¼1.5 Hz, 1H), 4.55 (dd, J¼3.3,
1.8 Hz 1H), 4.35 (m, 2H), 4.09 (AB d, J¼15.0 Hz, 1H),
4.00 (AB d, J¼15.0 Hz, 1H), 1.45 (d, J¼6.2 Hz, 3H),
1.37 (d, J¼6.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) (a-
anomer) d 165.9, 165.7, 165.4, 165.3 (CO), 161.4
(Cl3CC]NH), 133.4–133.1 (Cipso), 129.9–128.4 (C-Ar),
99.9, 95.8 (CA1 , C1B), 77.2, 74.3, 72.5, 71.8, 71.6, 71.5,
71.0, 70.6, 69.3, 68.6 (CA2 , C2B, C3A, C3B, C4A, C4B, C5A, CB5 ),
40.3 (CH2Cl), 17.7, 17.3 (CA6 , CB6 ). Anal. Calcd: C 55.77,
H 4.15, N 1.48. Found: C 56.01, H 4.11, N 1.45.
3020, 2985, 2930, 1726, 1601, 1452 cmꢀ1 1H NMR
.
(CDCl3, 200 MHz) d 8.00–7.30 (m, 10H), 5.61–5.51
(m, 3H), 5.30 (br s, 1H), 4.46 (dq, J¼8.8, 6.4 Hz, 1H),
2.71–2.63 (m, 6H), 2.03 (s, 3H), 1.26 (t, J¼6.2 Hz, 3H),
1.21 (d, J¼6.4 Hz, 3H); 13C NMR (CDCl3, 50 MHz)
d 205.8 (CH2COCH3), 171.3 (OCOCH2CH2), 165.9–165.6
(PhCO), 133.6, 133.4 (Cipso), 130.0–128.4 (C-Ar), 81.6
(C1), 71.5, 71.4, 69.9, 66.6 (C2, C3, C4, C5), 37.2,
29.1, 27.5, 25.1 (COCH2CH2COCH3), 17.0 (C6), 14.4
(SCH2CH3). ESIMS for C27H30O8S (m/z): Mr (calcd)
514.17; Mr (found) 537.41 (M+Na)+. Anal. Calcd: C
63.02, H 5.88. Found: C 63.26, H 5.65.
3.1.8. Allyl (3,4-di-O-benzoyl-2-O-chloroacetyl-a-L-
rhamnopyranosyl)-(1/2)-(3,4-di-O-benzoyl-a-L-

E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
8481
3.1.10. Allyl (3,4-di-O-benzoyl-2-O-levulinoyl-a-L-rhamno-
pyranosyl)-(1/2)-3,4-di-O-benzoyl-a-L-rhamnopyrano-
side (17). A mixture of 3 (544 mg, 1.32 mmol) and 16
(1.018 g, 1.98 mmol) was coevaporated three times with
toluene, the residue was dried, and then mixed with freshly
2C4B, 2C5A, 2C5B), 37.8, 29.7, 27.9 (COCH2CH2COCH3),
17.7, 17.3 (2CA6 , 2C6B). ESIMS for C53H48F3NO15 (m/z):
Mr (calcd) 995.30; Mr (found) 1018.40 (M+Na)+. Anal.
Calcd: C 63.92, H 4.86, N 1.41. Found: C 63.67, H 4.72,
N 1.38.
˚
activated AW-300 4 A molecular sieves and NIS (282 mg,
2.43 mmol). The mixture was suspended in CH2Cl2
(4.0 mL) under an Ar atmosphere, rapidly cooled to ꢀ30 ꢁC,
and treated with TfOH (43 mL, 0.49 mmol). After 90 min
the reaction mixture was rapidly filtered over a Celite pad, di-
luted with CH2Cl2, and washed with 10% Na2S2O3 and 1 M
NaHCO3. The organic layer was collected, dried, and concen-
trated to give a residue that after column chromatography (7:2
petroleum ether/ethyl acetate) afforded 17 (946 mg, 83%) as
a white foam. [a]D +60.9 (c 1.0, CH2Cl2). IR (thin film,
3.1.12. Propyl (3,4-di-O-benzoyl-a-L-rhamnopyranosyl)-
(1/2)-(3,4-di-O-benzoyl-a-L-rhamnopyranosyl)-(1/
3)-(2,4-di-O-benzoyl-a-L-rhamnopyranosyl)-(1/3)-
(2,4-di-O-benzoyl-a-L-rhamnopyranosyl)-(1/2)-(3,4-
di-O-benzoyl-a-L-rhamnopyranosyl)-(1/2)-3,4-di-O-
benzoyl-a-L-rhamnopyranoside (21). A mixture of 4
(73 mg, 49 mmol) and 2 (195 mg, 0.20 mmol) was coevapo-
rated three times with toluene, the residue was dried, and
˚
then mixed with freshly activated AW-300 4 A molecular
NaCl) 3050, 3026, 1731, 1604, 1263 cmꢀ1
.
1H NMR
sieves, suspended under argon in CH2Cl2 (6.0 mL), and
stirred at 0 ꢁC. A 10 mg/mL solution of TMSOTf in
CH2Cl2 (50 mL, 2.2 mmol) was then added. After 3 h the re-
action mixture was quenched with some drops of Et3N. After
filtration over a Celite pad, the mixture was concentrated.
The residue was subjected to column chromatography (5:1
to 3:2 petroleum ether/ethyl acetate) to give a foamy residue
that was dissolved in CH2Cl2 (7.0 mL) and then treated with
a 26 mg/mL solution of hydrazinium acetate in MeOH
(1.0 mL, 0.28 mmol). After 2 h stirring at rt, the mixture
was concentrated; a column chromatography (7:1 toluene/
ethyl acetate) on the residue afforded 21 (82 mg, 77%) as
a white foam. [a]D +100.8 (c 2.0, CH2Cl2). IR (thin film,
(CDCl3, 200 MHz) d 8.03–7.28 (m, 20H), 5.97 (m, 1H),
5.82 (dd, J¼10.0, 3.4 Hz, 1H), 5.78 (dd, J¼10.0, 3.0 Hz,
1H), 5.63 (m, 2H), 5.50 (t, J¼10.0 Hz, 1H), 5.38 (d,
J¼17.2 Hz, 1H), 5.27 (d, J¼10.6 Hz, 1H), 5.02 (d,
J¼1.6 Hz, 1H), 4.96 (d, J¼1.4 Hz, 1H), 4.34–4.06 (m, 5H),
2.60 (s, 4H), 2.08 (s, 3H), 1.38 (d, J¼6.2 Hz, 3H), 1.30 (d,
J¼6.2 Hz, 3H); 13C NMR (CDCl3, 50 MHz) d 205.8
(CH2COCH3), 171.3 (OCOCH2), 165.9, 165.6, 165.5, 165.3
(PhCO), 133.6–133.2 (Cipso, OCH2CH]CH2), 130.1–128.4
(C-Ar), 117.9 (OCH2CH]CH2), 99.6, 97.8 (CA1 , C1B), 76.9,
72.1, 71.8, 71.2, 70.3, 69.7, 68.4, 67.6, 67.1 (CA2 , C2B, C3A,
CB3, CA4 , CB4, CA5 , CB5, OCH2CH]CH2), 37.9, 29.8, 28.0
(COCH2CH2COCH3), 17.7, 17.6 (CA6 , C6B). ESIMS for
C48H48O15 (m/z): Mr (calcd) 864.30; Mr (found) 887.41
(M+Na)+. Anal. Calcd: C 66.66, H 5.59. Found: C 66.86,
H 5.50.
NaCl) 3019, 2924, 1729, 1600, 1269 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz) d 8.11–7.25 (m, 60H, H-Ar), 5.82 (dd,
J¼10.0, 3.2 Hz, 1H), 5.61–5.52 (m, 5H), 5.41–5.34 (m,
4H), 5.29 (t, J¼9.6 Hz, 1H), 5.26 (br s, 1H), 5.15 (br s,
1H), 5.10 (br s, 1H), 5.00 (br s, 1H), 4.93 (br s, 1H), 4.91
(br s, 1H), 4.76 (br s, 1H), 4.57 (br s, 1H), 4.48 (dd,
J¼9.6, 3.2 Hz, 1H), 4.36 (m, 2H), 4.22 (m, 3H), 4.11 (m,
1H), 3.99–3.88 (m, 3H), 3.73 (m, 2H), 3.48 (dq, J¼9.4,
6.2 Hz, 1H), 1.70 (app sextet, J¼7.4 Hz, 2H), 1.37 (d,
J¼6.2 Hz, 3H), 1.33 (d, J¼6.0 Hz, 3H), 1.11 (d, J¼6.1 Hz,
3H), 0.99 (t, J¼7.4 Hz, 3H), 0.96 (d, J¼6.1 Hz, 3H), 0.84
(d, J¼6.2 Hz, 3H), 0.75 (d, J¼6.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 165.8–165.0 (PhCO), 133.9–133.3
(Cipso), 130.0–128.0 (C-Ar), 100.8, 100.7, 100.4, 99.3,
99.2, 98.9 (C1A, C1B, C1C, C1D, C1E, CF1), 77.6, 76.9, 76.3, 75.4,
74.8, 73.3, 73.0, 72.0–71.4, 70.6, 70.0, 69.8, 68.4–67.3
(C2A, CB2 , CC2 , CD2 , CE2, C2F, CA3 , CB3 , CC3 , C3D, C3E, CF3, CA4 , CB4 ,
CC4 , C4D, C4E, CF4, C5A, CB5 , CC5 , C5D, C5E, CF5, OCH2CH2CH3),
22.7 (OCH2CH2CH3), 17.4–16.9 (CA6 , CB6 , C6C, C6D, C6E,
CF6), 10.5 (OCH2CH2CH3). MALDI-MS for C123H116O37
(m/z): Mr (calcd) 2184.72; Mr (found) 2207.49 (M+Na)+.
Anal. Calcd: C 67.57, H 5.35. Found: C 67.80, H 5.22.
3.1.11. (3,4-Di-O-benzoyl-2-O-levulinoyl-a-L-rhamno-
pyranosyl)-(1/2)-3,4-di-O-benzoyl-L-rhamnopyranosyl
N-phenyl-trifluoroacetimidate (19). Compound 17
(838 mg, 0.97 mmol) was dissolved in 3:1 CH2Cl2/MeOH
(4.0 mL), PdCl2 (103 mg, 0.58 mmol) was then added, and
the mixture was vigorously stirred overnight. It was then fil-
tered over a Celite pad, diluted with CH2Cl2, and washed
with 5 M NaCl. The organic layer was dried and concen-
trated to give 14 (664 mg, 83%) that was then mixed with
˚
freshly powdered 4 A MS and suspended in CH2Cl2
(12 mL) under Ar atmosphere. The mixture was cooled
to 0 ꢁC and then treated with CF3C(NPh)Cl (148 mL,
1.26 mmol) and NaH (60% dispersion in mineral oil;
58 mg, 1.45 mmol). After 4 h the solution was concentrated
at 30 ꢁC. The residue was subjected to neutral alumina
(Brockman grade 1) column chromatography (6:1 petroleum
ether/ethyl acetate) to give 19 (577 mg, 72%; a/b¼1:1) as
a white foam. IR (thin film, NaCl) 3026, 3012, 2917,
1732, 1600, 1452 cmꢀ1
.
1H NMR (CDCl3, 300 MHz)
3.1.13. Ethyl 2,4-di-O-benzoyl-3-O-levulinoyl-1-thio-
a-L-rhamnopyranoside (24). Compound 23 (86 mg,
0.21 mmol) was dissolved in CH2Cl2 (1.0 mL) and levulinic
acid (172 mL, 2.07 mmol), DMAP (13 mg, 0.10 mmol), and
DIPC (326 mL, 2.07 mmol) were added in succession. The
mixture was stirred for 30 min at rt, then diluted with
CH2Cl2, and washed with water. The organic layer was dried
and concentrated to afford a residue that after column
chromatography (4:1 petroleum ether/ethyl acetate) gave
24 (96 mg, 89%) as a colorless oil. [a]D +11.5 (c 1.0,
CH2Cl2). IR (thin film, NaCl) 3058, 3020, 2928, 1726,
1599, 1452 cmꢀ1. 1H NMR (CDCl3, 200 MHz) d 8.12–7.41
d 8.08–6.84 (m, 50H), 6.40 (br s, 1H), 5.99 (br s, 1H),
5.88–5.43 (m, 11H), 5.13 (br s, 1H), 5.07 (br s, 1H), 5.04
(br s, 1H), 4.60–4.52 (m, 2H), 4.22–4.13 (m, 2H), 2.57 (s,
4H), 2.56 (s, 4H), 2.01 (s, 6H), 1.45 (d, J¼6.0 Hz, 3H),
1.22 (d, J¼6.0 Hz, 3H), 1.18 (d, J¼6.0 Hz, 3H), 1.15
(d, J¼6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 205.8
(CH2COCH3), 171.2 (OCOCH2), 165.8, 165.7, 165.4,
165.3 (PhCO), 143.2 (C]N), 133.4–133.1 (Cipso), 130.0–
115.3 (C-Ar), 99.3, 98.3, 95.5, 93.9 (2CA1 , 2C1B), 76.9,
76.8, 74.1, 73.3, 72.5, 72.0, 71.5, 71.4, 71.0, 70.5, 69.9,
69.8, 69.7, 69.5, 67.8, 67.1 (2CA2 , 2C2B, 2CA3 , 2C3B, 2C4A,

8482
E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
(m, 10H), 5.62 (br s, 1H), 5.51 (m, 2H), 5.39 (br s, 1H), 4.43
(dq, J¼9.0, 6.4 Hz, 1H), 2.71 (dt, J¼7.6, 3.8 Hz, 2H), 2.63
(dt, J¼7.6, 3.8 Hz, 2H), 2.48 (dq, J¼7.2, 3.2 Hz, 1H), 2.33
(dq, J¼7.2, 3.2 Hz, 1H), 2.00 (s, 3H), 1.30 (m, 6H); 13C
NMR (CDCl3, 50 MHz) d 205.7 (CH2COCH3), 171.5
(OCOCH2CH2), 165.6, 165.4 (PhCO), 133.4, 133.3 (Cipso),
129.8–128.4 (C-Ar), 82.0 (C1), 72.1, 71.8, 69.7, 67.1 (C2,
C3, C4, C5), 37.5, 29.2, 27.7, 25.4 (COCH2CH2COCH3,
SCH2CH3), 17.4 (C6), 14.7 (SCH2CH3). ESIMS for
C27H30O8S (m/z): Mr (calcd) 514.17; Mr (found) 537.29
(M+Na)+. Anal. Calcd: C 63.02, H 5.88. Found: C 62.95,
H 5.96.
NMR (CDCl3, 300 MHz) d 8.25–6.80 (m, 50H), 6.43 (br s,
1H), 6.08 (br s, 1H), 5.70–5.57 (m, 3H), 5.40–5.12 (m,
11H), 4.52 (dd, J¼10.0, 3.4 Hz, 1H), 4.16–4.07 (m, 3H),
2.38 (m, 4H), 2.25 (m, 4H), 1.88 (s, 3H), 1.40 (d,
J¼6.0 Hz, 3H), 1.27 (d, J¼6.0 Hz, 3H), 1.20 (d, J¼6.0 Hz,
3H), 1.18 (d, J¼6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 206.1 (CH2COCH3), 170.9 (OCOCH2), 165.8, 165.6,
165.5, 164.8 (PhCO), 143.0 (C]N), 133.7–133.3 (Cipso),
130.0–115.3 (C-Ar), 99.3, 94.1, 93.6 (2CA1 , 2C1B), 75.1,
72.4, 72.0, 71.3, 70.6, 70.1, 69.4, 68.9, 68.7, 67.6 (2CA2 ,
2CB2 , 2CA3 , 2CB3 , 2C4A, 2C4B, 2C5A, 2CB5 ), 37.6, 29.3, 27.7
(COCH2CH2COCH3), 17.7, 17.3 (2CA6 , 2C6B). ESIMS for
C53H48F3NO15 (m/z): Mr (calcd) 995.30; Mr (found)
1018.29 (M+Na)+. Anal. Calcd: C 63.92, H 4.86, N 1.41.
Found: C 63.59, H 4.74, N 1.38.
3.1.14. Allyl (2,4-di-O-benzoyl-3-O-levulinoyl-a-L-rhamno-
pyranosyl)-(1/3)-2,4-di-O-benzoyl-a-L-rhamnopyrano-
side (26). A mixture of 25 (53 mg, 0.13 mmol) and 24 (86 mg,
0.17 mmol) was coevaporated three times with toluene, the
residue was dried, and then mixed with freshly activated
3.1.16. Propyl a-L-rhamnopyranosyl-(1/3)-a-L-rham-
nopyranosyl-(1/2)-a-L-rhamnopyranosyl-(1/2)-a-L-
rhamnopyranosyl-(1/3)-a-L-rhamnopyranosyl-(1/
3)-a-L-rhamnopyranosyl-(1/2)-a-L-rhamnopyranosyl-
(1/2)-a-L-rhamnopyranoside (28). A mixture of 21
(40 mg, 18 mmol) and 22 (72 mg, 72 mmol) was coevapo-
rated three times with toluene, the residue was dried, and
˚
AW-300 4 A molecular sieves and NIS (47 mg, 0.21 mmol).
The mixture was suspended in CH2Cl2 (4.0 mL) under an Ar
atmosphere, rapidly cooled to ꢀ30 ꢁC, and treated with
TfOH (5.5 mL, 63 mmol). After 3 h the reaction mixture was
rapidly filtered over a Celite pad, diluted with CH2Cl2, and
washed with 10% Na2S2O3 and 1 M NaHCO3. The organic
layer was collected, dried, and concentrated to give a residue
that after column chromatography (10:1 to 8:1 toluene/ethyl
acetate) afforded 26 (97 mg, 87%) as a white foam. [a]D
+84.4 (c 1.0, CH2Cl2). IR (thin film, NaCl) 3052, 3026,
˚
then mixed with freshly activated AW-300 4 A molecular
sieves, suspended under argon in CH2Cl2 (3.0 mL), and
stirred at 0 ꢁC. An 8.2 mg/mL solution of TMSOTf in
CH2Cl2 (50 mL, 1.8 mmol) was then added. After stirring
the reaction mixture at 0 ꢁC overnight, some drops of Et3N
were added. The mixture was filtered over a Celite pad and
concentrated. The residue was subjected to column chroma-
tography (10:1 to 8:1 toluene/ethyl acetate) to give a foamy
residue that was dissolved in 3:1 MeOH/CH2Cl2 (2.0 mL)
and then treated with a 3.5 M methanolic solution of NaOMe
(90 mL, 0.31 mmol). The solution was heated to 40 ꢁC and
stirred at this temperature over 2 days; it was then neutralized
with Amberlist-15 H+, filtered, and concentrated. The residue
was subjected to a gel-filtration chromatography to give 28
1733, 1604, 1263 cmꢀ1 1H NMR (CDCl3, 200 MHz)
.
d 8.23–7.32 (m, 20H), 5.92 (m, 1H), 5.57 (t, J¼9.8 Hz, 1H),
5.52 (m, 2H), 5.42–5.21 (m, 3H), 5.16 (br s, 2H), 5.05 (br s,
1H), 4.48 (dd, J¼10.0, 3.4 Hz, 1H), 4.24 (ddt, J¼12.8, 5.0,
1.2 Hz, 1H), 4.14–4.00 (m, 3H), 2.37 (dt, J¼7.4, 3.8 Hz,
2H), 2.23 (dt, J¼7.4, 3.8 Hz, 2H), 1.86 (s, 3H), 1.35 (d,
J¼6.2 Hz, 3H), 1.16 (d, J¼6.1 Hz, 3H); 13C NMR (CDCl3,
50 MHz) d 205.6 (CH2COCH3), 170.6 (OCOCH2CH2),
166.0, 165.6, 165.4, 164.8 (PhCO), 133.4, 133.1 (Cipso
,
1
OCH2CH]CH2), 129.8–128.3 (C-Ar), 117.8 (OCH2CH]
CH2), 99.1, 96.3 (CA1 , C1B), 75.9, 73.0, 72.2, 71.3, 70.2, 68.7,
68.4, 67.2, 66.7 (CA2 , CB2 , C3A, C3B, C4A, CB4 , C5A, CB5 ,
OCH2CH]CH2), 37.5, 29.2, 27.6 (COCH2CH2COCH3),
17.5, 17.2 (C6A, C6B). ESIMS for C48H48O15 (m/z): Mr (calcd)
864.30; Mr (found) 887.48 (M+Na)+. Anal. Calcd: C 66.66,
H 5.59. Found: C 66.95, H 5.65.
(10.8 mg, 49%) as a white wax. [a]D +81 (c 0.6, H2O). H
NMR (D2O, 400 MHz) d 5.19 (br s, 1H, HE1), 5.12 (br s,
1H, HF1), 5.11 (br s, 1H, H1B), 5.04 (br s, 1H, HH1 ), 5.02 (br s,
1H, HD1 ), 4.96 (br s, 2H, H1C, H1G), 4.87 (br s, 1H, HA1 ), 4.15
(m, 3H, HC2 , HD2 , H2G), 4.08 (m, 4H, HB2 , HE2, H2F, HH2 ), 3.96
(dd, J3,4¼9.8 Hz, J3,2¼3.2 Hz, 1H, HE3), 3.92–3.82 (m, 9H,
HA2 , HA3 , HB3 , HC3 , H3D, H3F, H3G, H3H, HE5), 3.77–3.72 (m, 8H,
HA5 , HB5 , HC5 , HD5 , H5F, H5G, H5H), 3.65 (dt, Jgem¼13.9 Hz,
Jvic¼6.5 Hz, 1H, OCHHCH2CH3), 3.56–3.46 (m, 9H, HA4 ,
HB4 , HC4 , HD4 , HE4, H4F, H4G, H4H, OCHHCH2CH3), 1.61 (app
sextet, J¼7.0 Hz, 2H, OCH2CH2CH3), 1.29 (m, 24H, HA6 ,
HB6 , HC6 , HD6 , H6E, H6F, H6G, HH6 ), 0.91 (t, J¼7.0 Hz, 3H,
OCH2CH2CH3); 13C NMR (D2O, 100 MHz) d 103.0 (CD1 ,
CH1 ), 102.7 (C1C, CG1 ), 101.6 (C1E), 101.5 (CB1 , C1F), 98.9 (CA1 ),
79.0 (CA2 ), 78.9 (C2B, C2E, CF2), 78.8 (C3C, C3G), 78.3 (CD3 ),
72.9 (CA4 , CB4 , C4E, C4F, C4H), 72.0 (C4C, CD4 , C4G), 70.6 (CE3),
70.4 (CA3 , CH3 , CE5), 70.3 (C3B, CH3 , OCH2CH2CH3), 70.1
(C5B, CC5 , CD5 , C5F, C5G, C5H), 69.8 (CA5 ), 22.5 (OCH2CH2CH3),
17.4 (CA6 , CB6 , C6C, C6D, C6E, C6F, CG6 , CH6 ), 10.4 (OCH2CH2CH3).
MALDI-MS for C51H88O33 (m/z): Mr (calcd) 1228.52; Mr
(found) 1251.15 (M+Na)+. Anal. Calcd: C 49.83, H 7.22.
Found: C 49.59, H 7.44.
3.1.15. (2,4-Di-O-benzoyl-3-O-levulinoyl-a-L-rhamno-
pyranosyl)-(1/2)-2,4-di-O-benzoyl-L-rhamnopyranosyl
N-phenyl-trifluoroacetimidate (22). Compound 26
(178 mg, 0.21 mmol) was dissolved in 3:1 CH2Cl2/MeOH
(4.0 mL), PdCl2 (19 mg, 0.11 mmol) was then added, and
the mixture was vigorously stirred overnight. It was then fil-
tered over a Celite pad, diluted with CH2Cl2, and washed
with 5 M NaCl. The organic layer was dried and concentrated
to give 27 (104 mg, 60%) that was then mixed with freshly
˚
powdered 4 A MS and suspended in CH2Cl2 (6.0 mL) under
Ar atmosphere. The mixture was cooled to 0 ꢁC and then
treated with CF3C(NPh)Cl (19 mL, 0.16 mmol) and NaH
(60% dispersion in mineral oil; 7.6 mg, 0.19 mmol). After
4 h the solution was concentrated at 30 ꢁC. The residue was
subjected to neutral alumina (Brockman grade 1) column
chromatography (10:1 to 5:1 petroleum ether/ethyl acetate)
to give 22 (73 mg, 58%; a/b¼1:1) as a white foam. IR (thin
3.1.17. Allyl a-L-rhamnopyranosyl-(1/3)-a-L-rhamno-
pyranosyl-(1/2)-a-L-rhamnopyranosyl-(1/2)-a-L-
rhamnopyranoside (29). A solution of 1 (24 mg, 15.5 mmol)
1
film, NaCl) 3028, 3012, 2925, 1728, 1595, 1452 cmꢀ1. H

E. Bedini et al. / Tetrahedron 62 (2006) 8474–8483
8483
in MeOH (1.0 mL) was treated with a 0.7 M methanolic so-
Acknowledgements
lution of NaOMe (500 mL, 0.35 mmol). The solution was
heated to 40 ꢁC and stirred at this temperature overnight;
it was then neutralized with Amberlist-15 H+, filtered, and
concentrated. The residue was subjected to a gel-filtration
chromatography to give 29 (7.8 mg, 78%) as a white wax.
We thank MIUR, Rome (Progetti di Ricerca di Interesse
Nazionale 2004, M.P.) for the financial support. The
NMR spectra were performed at CIMCF (Centro di
Metodologie Chimico-Fisiche) of University ‘Federico II’
of Naples.
1
[a]D +25 (c 0.5, H2O). H NMR (D2O, 400 MHz) d 6.12
(m, 1H, OCH2CH]CH2), 5.52 (d, J¼17.2 Hz, 1H, trans
OCH2CH]CHH), 5.47 (d, J¼10.4, 1H, cis OCH2CH]
CHH), 5.25 (br s, 1H, H-1B), 5.20 (br s, 1H, H-1D), 5.12
(br s, 1H, H-1C), 5.08 (br s, 1H, H-1A), 4.40 (br d,
J¼5.1 Hz, 1H, OCHHCH]CH2), 4.37 (br d, J¼5.1 Hz,
1H, OCHHCH]CH2), 4.31 (br s, 1H, HC2 ), 4.25 (br s, 1H,
HB2 ), 4.22 (br s, 1H, H2D), 4.09 (br s, 1H, HA2 ), 4.07–3.96
(m, 5H, HA3 , HB3 , H3C, H3D, H5D), 3.93–3.86 (m, 3H, H5A, HB5 ,
HC5 ), 3.70 (t, J¼9.8 Hz, 1H, H4C), 3.63 (m, 3H, H4A, HB4 ,
HD4 ), 1.45 (m, 12H, H6A, H6B, HC6 , H6D); 13C NMR (D2O,
100 MHz) d 133.5 (OCH2CH]CH2), 119.1 (OCH2CH]
CH2), 102.8 (C1D), 102.4 (C1C), 101.4 (C1B), 97.7 (C1A), 78.9
(CA2 ), 78.5 (CB2 ), 78.4 (C2C), 72.5–72.4 (CA4 , C4B, CD4 ), 71.6
(CC4 ), 70.5–70.1 (C2C, CD2 , C3A, CB3 , CD3 , C5D), 69.7 (CC5 ), 69.6
(C5A), 69.5 (C5B), 68.6 (OCH2CH]CH2), 17.0–16.9 (CA6 ,
CB6 , CC6 , CD6 ). MALDI-MS for C27H46O17 (m/z): Mr (calcd)
642.27; Mr (found) 643.49 (M+Na)+. Anal. Calcd: C 50.46,
H 7.21. Found: C 50.20, H 7.36.
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pyranosyl-(1/3)-a-L-rhamnopyranosyl-(1/3)-a-L-
rhamnopyranosyl-(1/2)-a-L-rhamnopyranosyl-(1/2)-
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9.7 mmol) in 3:1 MeOH/CH2Cl2 (2.0 mL) was treated with a
3.5 M methanolic solution of NaOMe (90 mL, 0.31 mmol).
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1
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(D2O, 400 MHz) d 5.96 (m, 1H, OCH2CH]CH2), 5.36 (d,
J¼17.2, 1H, trans OCH2CH]CHH), 5.31 (d, J¼10.4 Hz,
1H, cis OCH2CH]CHH), 5.22 (br s, 1H, HE1), 5.10 (br s,
1H, HB1 ), 5.02 (br s, 1H, H1D), 4.96 (br s, 2H, H1C, HF1), 4.92
(br s, 1H, HA1 ), 4.24 (br d, J¼5.1 Hz, 1H, OCHHCH]CH2),
4.21 (br d, J¼5.1 Hz, 1H, OCHHCH]CH2), 4.17 (br s, 1H,
HC2 ), 4.14 (br s, 1H, H2D), 4.11 (br s, 1H, HB2 ), 4.08 (br s, 2H,
HE2, HF2), 4.01–3.77 (m, 13H, HA2 , HA3 , HB3 , H3C, H3D,
HE3, HF3, HA5 , H5B, H5C, H5D, HE5, HF5), 3.58 (m, 2H, HC4 , H4D),
3.51–3.44 (m, 4H, HA4 , H4B, H4E, H4F), 1.29 (m, 18H, HA6 ,
HB6 , HC6 , H6D, H6E, H6F); 13C NMR (D2O, 100 MHz) d 133.9
(OCH2CH]CH2), 119.5 (OCH2CH]CH2), 103.0 (CD1 ),
102.9 (CC1 , CF1), 101.7 (C1B, C1E), 98.0 (C1A), 79.3 (CA2 ), 79.0
(CE2), 78.9 (CB2 ), 78.8 (C3C), 78.5 (CD3 ), 72.8–72.2 (C4A, CB4 ,
CC4 , CD4 , C4E, C4F), 70.7–70.5 (C2C, CD2 , CF2, CA3 , C3B, CE3 C3F,
CC5 ), 70.0–69.8 (CA5 , C5B, CD5 , CE5, C5F), 68.9 (OCH2CH]
CH2), 17.4–17.3 (CA6 , C6B, C6C, C6D, C6E, CF6). MALDI-MS
for C39H66O25 (m/z): Mr (calcd) 934.39; Mr (found) 935.41
(M+H)+. Anal. Calcd: C 50.10, H 7.12. Found: C 49.91,
H 7.29.
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