D-glucose as a regioselectively addressable scaffold for combinatorial chemistry on solid phase

Article abstract of DOI:10.1081/CAR-120019014

D-Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on secondary hydroxyl groups were linked to solid supports (PS/DV polymer, tentagel resin) through an ester bond on C-6. It was investigated the possibility to remove orthogonally protecting groups and functionalize selectively the free hydroxyls groups and the anomeric carbon of sugars in solid phase.

Full text of DOI:10.1081/CAR-120019014

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d‐Glucose as a Regioselectively Addressable Scaffold
for Combinatorial Chemistry on Solid Phase
Dr. Francesco Peri a , Dr. Francesco Nicotra a , Colin P. Leslie b , Fabrizio Micheli b ,
Pierfausto Seneci b & Carla Marchioro b
a Department of Biotechnology and Biosciences , University of Milano–Bicocca , Piazza Della
Scienza, 2, I‐20126, Italy
b Medicines Research Centre , GlaxoSmithKline SpA , Via Fleming 4, Verona, 37135, Italy
Published online: 20 Aug 2006.
To cite this article: Dr. Francesco Peri , Dr. Francesco Nicotra , Colin P. Leslie , Fabrizio Micheli , Pierfausto Seneci & Carla
Marchioro (2003) d‐Glucose as a Regioselectively Addressable Scaffold for Combinatorial Chemistry on Solid Phase, Journal of
Carbohydrate Chemistry, 22:1, 57-71, DOI: 10.1081/CAR-120019014
To link to this article: http://dx.doi.org/10.1081/CAR-120019014
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, No. 1, pp. 57–71, 2003
D-Glucose as a Regioselectively Addressable Scaffold
for Combinatorial Chemistry on Solid Phase
1,
2
Francesco Peri,1, Francesco Nicotra, Colin P. Leslie,
*
*
Fabrizio Micheli,2 Pierfausto Seneci,2 and Carla Marchioro2
1Department of Biotechnology and Biosciences, University of Milano–Bicocca,
Piazza Della Scienza,
2GlaxoSmithKline SpA, Medicines Research Centre,
Verona, Italy
ABSTRACT
D-Glucose derivatives bearing an anomeric thiophenyl group and orthogonally
protections on secondary hydroxyl groups were linked to solid supports (PS/DV
polymer, tentagel resin) through an ester bond on C-6. It was investigated the
possibility to remove orthogonally protecting groups and functionalize selectively the
free hydroxyls groups and the anomeric carbon of sugars in solid phase.
Key Words: Combinatorial chemistry; Sugars; Solid phase; Scaffolds.
INTRODUCTION
D-Glucose is a readily available, chiral and highly functionalized compound which
displays, in the pyranose form, conformational rigidity and five different hydroxyl groups
in a well defined spatial arrangement. These characteristics make glucose an attractive
scaffold for designing primary screening libraries. Following this observation,
*
Correspondence: Dr. Francesco Peri and Dr. Francesco Nicotra, Department of Biotechnology
and Biosciences, University of Milano–Bicocca, Piazza Della Scienza, 2; I-20126, Italy; E-mail:
francesco.peri@unimib.it and francesco.nicotra@unimib.it.
57
DOI: 10.1081/CAR-120019014
0732-8303 (Print); 1532-2327 (Online)
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Copyright D 2003 by Marcel Dekker, Inc.

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58
Peri et al.
nonpeptidal peptidomimetics derived from glucose have been developed as efficient
antagonists of the hormone somatostatin,[1,2] and as b-adrenergic and NK-1 antagonists.[3]
The decoration of monosaccharides by differential derivatization of the hydroxyl
groups is particularly suitable for developing libraries by a combinatorial approach,
once the protected sugar is linked to a polymer through the C-1 or C-6 hydroxyl
groups.[4] The regioselective functionalization of the hydroxyl groups in solid phase
must be accomplished by a sequence of selective deprotection-coupling steps.
To efficiently carry out such combinatorial syntheses, the choice of a convenient set
of mutually orthogonal protecting groups, selectively removable without affecting the
resin linker and resistant to the reaction conditions commonly employed during organic
synthesis, is of crucial importance. Such requirements represent a real synthetic challenge,
considering that only a fraction of the known hydroxyl protecting groups are compatible
with solid phase chemistry. Several orthogonal protection schemes have been adapted
from the solid phase strategies developed for the synthesis of oligosaccharides[4] and
improved in order to maximize the number of diversity sites. Up to three orthogonal
hydroxyl protecting groups for D-glucose[5] and five for D-galactose,[6] bound to resin
through a thioglycoside anchor, have been employed. Orthogonally protected D-glucose
was linked with four different glycosyl donors, using an efficient deprotection–glyco-
sylation procedure in solution, affording a library of branched oligosaccharides.[7]
Synthetic strategies compatible with solid phase chemistry have been validated in solution
for D-glucose scaffolds presenting a high degree of diversity.[8] The problem of extensive
orthogonalities has been partially circumvented by using aminoglucuronic acids.[9] The
carboxylic group of the sugar can be exploited to link the solid support, and the amino
group of the sugar allows an enlarged choice of orthogonal protecting groups.
The flexible strategy of glycal assembly for solid phase glycosidation developed by
Danishefsky[10] and co-workers inspired the use of monosaccharide scaffolds with
oxirane rings. An anhydrosugar with an oxirane ring was anchored to the polymer, and
two sites of diversity were accessed on solid phase by epoxide-opening reactions.[11]
Despite the remarkable progresses recently achieved in this field, the complete ortho-
gonality between identical functional groups is a major problem in combinatorial syn-
theses and the efficient extension of solution protection/deprotection techniques to
polymer-bound sugars still represents a frontier for the organic chemist.
In this context, we planned to develop a system in which b-D-glucopyranose plat-
forms are linked to a polymer through an ester bond involving the OH-6 group, ortho-
Figure 1. Thioglucosides 1, 2 and 3 and their polymer-bound analogues.

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D-Glucose as Scaffold
59
gonally protected on the secondary hydroxyls and activated as thioglucosides at the
anomeric position. We tested the efficiency of the orthogonal set chosen and of the
functionalisation reactions on a model compound in solution, then we extended the re-
activity study to the same scaffold bound to PEG and polystyrene/divinylbenzene resins.
RESULTS AND DISCUSSION
Thioglucosides 1 and 2 were prepared, having the same set of orthogonal groups but
with different regiochemistry (Figure 1). Both monosaccharides were bound to the
Tentagel resin (1a and 2a) through an ester linkage, and to the PS/DV polymer through
a succinamide linkage (1b and 2b). Compound 1 was functionalized with an N-
benzylamidosuccinyl appendage at C-6, to give the model compound 3 which mimics
the sugar-linker system of 1b and 2b. The hydroxyl protecting groups chosen for this
study, the p-methoxybenzyl (PMB) and the allyl (All) group, can be removed,
respectively, by oxidative cleavage (DDQ) and double bond isomerisation followed by
acid hydrolysis of the enol ether. In addition to these two groups, a free hydroxyl group
is present in both glucosides (at C-2 in 1 and C-3 in 2) as a third functionalizable site.
Finally, both thioglucosides can be activated as sulfoxides and a fourth group can be
introduced at the anomeric position. We verified the orthogonality efficiency under the
experimental conditions employed for deprotection and functionalisation of the four
hydroxyl groups of the sugars ( at C-1, C-2, C-3, C-4), and for anchoring/cleavage to/
from solid supports through an ester linkage. We also compared the reactivity of model
compound 3 in solution with that of compounds 1a and 1b on solid phase. Thio-
glucoside 1 was prepared according to the synthetic strategy shown in Scheme 1.
1,2,4,6-Tetra-O-acetyl-3-O-allyl-b-D-glucopyranose 4 was obtained from the commer-
cially available 1,2,5,6-diisopropylidene-D-glucofuranose by allylation at C-3 (93%),
Scheme 1. i: Allyl bromide, NaH, DMF; ii: Amberlite IR-120 H + , MeOH–H2O; iii: Ac2O, py,
DMAP; iv: PhSH, BF3–Et2O, CH2Cl2; v: MeONa, MeOH; vi: Anisaldehyde dimethyl acetal,
p-TSA, CH3CN; vii: LiAlH4–AlCl3, CH2Cl2/Et2O.

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60
Peri et al.
followed by acid hydrolysis of the acetonide groups (98%) and acetylation (98%).[12]
Compound 4 was transformed into phenyl 2,4,6-tri-O-acetyl-3-O-allyl-1-thio-b-D-
glucopyranoside (5) by BF3–Et2O catalysed reaction with thiophenol in dry CH2Cl2
(82%). Treatment of 5 with MeONa in dry MeOH afforded compound 6 (97%), which
upon reaction with anisaldehyde dimethyl acetal in dry MeCN with a catalytic amount
of p-TSA gave compound 7 (94%), in which both the C-4 and C-6 hydroxyl groups are
protected as a p-methoxybenzylidene (PMB) acetal. Several attempts to protect the free
C-2 hydroxyl group of compound 7 as ether, silyl ether or ester, employing different
experimental conditions, were unsuccessful and indicated the very low reactivity of this
hydroxyl group. As a consequence we decided to maintain this hydroxyl group
unprotected in the subsequent solid-phase approach. The p-methoxybenzylidene acetal
of 7 was finally reduced with LiAlH4–AlCl3 in dry CH2Cl2/Et2O, to install re-
gioselectively a PMB ether at C-4 and to liberate the primary hydroxyl group at C-6,
yielding phenyl 3-O-allyl-4-O-p-methoxybenzyl-1-thio-b-D-glucopyranoside (1) (98%
yield). Phenyl 2-O-allyl-4-O-p-methoxybenzyl-1-thio-b-D-glucopyranoside (2) was ob-
tained using a similar synthetic pathway (Scheme 2). Phenyl 2,3,4,6-tetra-O-acetyl-1-
thio-b-D-glucopyranoside[13,14] was deacetylated (MeONa in MeOH, 97%) to furnish
phenyl 1-thio-b-D-glucopyranoside, which was converted into its PMB acetal 8[15]
(90%). Reaction of 8 with tert-butyldimethylsilyl (TBDMS) chloride in the presence of
imidazole resulted in a totally regioselective silylation at C-3 affording compound 9 in
94% yield. This result is consistent with the very low reactivity of the hydroxyl group at
C-2 observed in derivative 7. Compound 9 was then allylated to give compound 10
(70%), treatment of which with LiAlH4–AlCl3 in dry CH2Cl2/Et2O led to regioselective
reductive opening of the acetal and concomitant hydrolysis of the silyl ether to afford
phenyl 2-O-allyl-4-O-p-methoxybenzyl-1-thio-b-D-glucopyranoside (2) (82%). In a first
screening of the best resin-linker system to support compounds 1 and 2 for solid phase
transformations, we excluded the possibility of linking the sugars to resins through an
acid-labile bond, because acid conditions (due to the use of Lewis acid promoters) are
Scheme 2. i: TBDMS–Cl, Imidazole, CH2Cl2; ii: Allyl bromide, NaH, DMF; iii: LiAlH4–AlCl3,
CH2Cl2/Et2O.

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D-Glucose as Scaffold
61
Scheme 3. Loading on PS/DV and Tentagel resins of thioglucosides 1 and 2.
required in the most common methods for solid phase glycosylations.[4] Moreover, both
allyl and PMB groups are acid-labile, but resistant to basic conditions. For this reason,
we investigated the loading of substrates 1 and 2 onto carboxylic Tentagel and
polystyrene-divinylbenzene resins through a base-labile ester linker. Compounds 1 and
2, DIC, HOBt, DMAP and pyridine were reacted with carboxy-Tentagel (Novabiochem,
0.27 mmol/g) or carboxy-polystyrene (Novabiochem, 1.24 mmol/g) resins in dry DMF
Scheme 4. Orthogonal deprotection of secondary xydroxyl groups on model compound 3.

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62
Peri et al.
Scheme 5. Functionalization as BOM ether of polymer-bound substrate 2a.
under an argon atmosphere. A loading value of about 0.2 mmol/g for both 1 and 2 was
found for Tentagel resin (calculated gravimetrically on crude sugars cleaved from resins
with a mixture of 2% aqueous NaOH and dioxane), while a negligible amount of both
sugars loaded onto polystyrene resin even when employing longer reaction times or
repeating the loading procedure (Scheme 3). The very low reactivity of the carboxy-PS/
DV resin with compounds 1 and 2 is probably due to the absence of a spacer between
the reactive carboxylic group and the polymer bulk of the resin. To overcome this
problem, compounds 1 and 2 were functionalised at C-6 with a succinate linker and then
reacted with an amino-polystyrene resin (Novabiochem, 1.13 mmol/g) in the presence of
HBTU, HOBt and DIPEA in dry DMF, thus yielding resins 1b and 2b with acceptable
loading values (about 0.9 mmol/g). The low reactivity of free hydroxyl groups at C-2 or
C-3 in 1 and 2, respectively, ensured the selective attachment of sugar to polymer
through the C-6 position. This was confirmed, in the case of the Tentagel resin
derivatives, by the observation that MAS 1H NMR spectra of solids 1a and 2a
correspond to homogeneous C-6 linked sugars. Model compound 3 was submitted to
orthogonal deprotection at positions C-4 (affording 3b) and C-2 (affording 3c) and
activation of the anomeric position as sulfoxide (affording 3a) as depicted in Scheme 4.
The very low reactivity of the free hydroxyl group at C-2 was once more confirmed by
the failure of 3 to undergo acetylation (Ac2O, pyridine and DMAP, rt) or carbamate
formation (phenyl isocyanate, DMAP, rt). Etherification at C-2 by using benzyl bromide
and NaH turned out to be incompatible with the succinate linker, the ester bond being
hydrolyzed affording a mixture of mono- and dialkylated products. Unfortunately, the
ester bond of 3 was also cleaved when benzyl trichloroacetimidate was used as
alkylating agent in the presence of Lewis acids TMSOTf or BF3–Et2O. In this case a
complex mixture of products was formed. The oxidation of 3 to the sulfoxide 3a was
carried out in good yield using m-CPBA in dry CH2Cl2 (82% yield). As an example of
solid phase derivatization on Tentagel resin, compound 2a was functionalised at C-3 as
its benzyloxymethyl (BOM) ether (Scheme 5). Resin 2a was reacted with BOM
chloride, TBAI and DIPEA in dry DMF, giving, after cleavage from the resin (2%
NaOH/dioxane), compound 11 in 98% yield. Alkyloxy halides are more reactive than
the corresponding alkyl halides and alkylation proceeds on the free OH in the presence
of weak bases (such as DIPEA). Under these conditions it is possible to form the ether at
C-3 avoiding the hydrolysis of the ester linker. The regioisomer 1a did not react under
the same reaction conditions, thus indicating that the reactivity of the free hydroxyl
group at C-2 in this compound is lower than that of C-3 hydroxyl group in 2a. The
experimental data collected on compounds 1a and 2a bound to Tentagel resin, suggested

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D-Glucose as Scaffold
63
exploring the possibility of functionalizing 1b and 2b on solid phase as BOM ethers.
Only 2b reacted forming the BOM ether at C-2 in high yield (92% yield), while 1b did
not react under the same conditions, mirroring the results obtained with Tentagel-bound
glucosides 1a and 2a.
CONCLUSIONS
In summary we reported the efficient loading of two phenyl thioglucosides,
protected with the same set of orthogonal groups, onto Tentagel and PS/DV resins. The
base-labile ester linker, used to anchor the thioglucosides to the resin through the C-6
position, allowed the use of acidic conditions for hydroxyl group deprotection. p-
Methoxybenzyl and allyl protecting groups were found to be completely orthogonal,
and the derivatization of the free hydroxyl groups of the sugars via alkoxymethyl ethers
was carried out on solid phase with good yields. Despite the elevated number of known
hydroxyl protecting groups, the development of polymer-bound sugars presenting three
or four really independent functionalisation sites, is still a challenging task. Both
glucosides 1 and 2, were planned to have four orthogonal sites once linked to a
polymer through C-6. The deprotection–functionalization experiments showed that
sugar 1 in polymer-bound 1a and 1b presents three effective orthogonal sites including
the anomeric position. Glucoside 2, in derivatives 2a and 2b, was first derivatized at C-
3 as a BOM ether. The C-2 and C-4 positions offer two other orthogonal sites, so that
including the anomeric C-1, compound 2 presents four diversity sites on solid phase.
The reactivity of the anomeric positions of 1 and 2 on solid phase and the
development of libraries based on these scaffolds, are currently being investigated and
will be reported in due course.
EXPERIMENTAL
General procedures. All solvents were dried over molecular sieves (Fluka), for
at least 24 h prior to use. Resins for solid phase synthesis were purchased from
Novabiochem (Laufelfingen, CH). Thin-layer chromatography (TLC) was performed on
Silica Gel 60 F254 plates (Merck) with detection with UV light when possible, or
charring with a solution containing conc. H2SO4/MeOH/H2O in a ratio of 5/45/45.
Flash column chromatography was performed on silica gel 230–400 mesh (Merck).
Usual workup refers to dilution with an organic solvent, washing with water to
neutrality (pH test paper), drying with Na2SO4, filtration, and evaporation of solvent
1
under reduced pressure. H and 13C NMR spectra were recorded on a Varian Mercury
1
1
400 (400 MHz for H and 100.62 MHz for 13C) and Bruker AC300 (300 MHz for H
and 75.47 MHz for 13C) spectrometers, using TMS as the internal standard. Aromatic
carbons are omitted in the description of 13C spectra. [a]D values were measured at
20°C on a Perkin Elmer 241 digital polarimeter and are given in units of 10 À 1 deg
cm2 g À 1. Mass spectra were recorded on a MALDI 2 Kompakt Kratos instrument,
using gentisic acid (DHB) as matrix. Elemental analyses were performed with a
Perkin–Elmer Series II Analyzer 2400.

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Peri et al.
Phenyl 2,4,6-Tri-O-acetyl-3-O-allyl-1-thio-b-D-glucopyranoside (5). To a solu-
tion of 1,2,4,6-tetra-O-acetyl-3-O-allyl-b-D-glucopyranose 4 (1 g, 2.58 mmol) in dry
CH2Cl2 (20 mL), thiophenol (3.87 mmol, 394 mL) and BF3–Et2O (3.87 mmol, 483 mL)
were added under an argon atmosphere. The reaction mixture was stirred for 12 h at rt
(monitoring by TLC, AcOEt/petroleum ether 1:1). The crude product was then diluted
with dichloromethane, and after usual workup purified by FC (AcOEt/petroleum ether
1:1), affording compound 5 as a white solid (0.96 g, 82% yield).
25°
1
[a]D
+ 49.7 (c 1, CHCl3). H NMR (300 MHz, CDCl3): d(ppm) 7.50–7.20 (m,
5H, Harom), 5.75 (ddd, 1H, J1’–2’ = 6.5 Hz, J2’–3’cis = 10.8 Hz, J2’–3’trans = 15.95 Hz, H-
2’), 5.17 (bd, 1H, J2’–3’trans = 15.9 Hz, H-3’), 5.10 (bd, 1H, J2’–3’cis = 10.8 Hz, H-3’),
5.00 (t, 1H, J1–2 = J2–3 = 9.6 Hz, H-2), 4.98 (t, 1H, J3–4 = J4–5 = 9.3 Hz, H-4), 4.61
(d, 1H, J1–2 = 10.4 Hz, H-1), 4.20–4.00 (m, 4H, 2H-6 and 2H-1’), 3.59 (t, 1H, J3–4 = J2–
= 9.3 Hz, H-3), 3.58 (m, 1H, H5), 2.10–2.00 (3s, 9H, CH3). 13C NMR (100 MHz,
3
CDCl3): d(ppm) 171.2, 168.1, 167.9, 134.3, 117.2, 86.4, 81.5,76.3, 73.4, 71.6, 69.8, 62.9,
21.4, 21.3, 21.2. MS (MALDI-TOF): 439.2 (M + H), 478.6 (M + K).
Anal. Calcd for C21H26O8S: C, 57.52; H, 5.98; S, 7.31. Found: C, 58.09; H, 5.77;
S, 7.88.
Phenyl 3-O-Allyl-1-thio-b-D-glucopyranoside (6). To a vigorously stirred
solution of compound 5 (3 g, 6.85 mmol) in dry MeOH (50 mL), a catalytic amount
of metallic sodium was added under an argon atmosphere. After 12 h at rt hydrolysis of
all acetates was complete as assessed by TLC ( AcOEt/petroleum ether 4:6). Amberlite
IR 120 H + was then added and stirring continued until the solution reached a neutral
pH. The resin was then removed by filtering, the solvent evaporated, and pure
25°
compound 6 was recovered as a colourless oil (2.09 g, 98% yield). [a]D
+ 21.1
(c 0.8, MeOH).1H NMR (300 MHz, d-MeOH): d(ppm) 7.60–7.30 (m, 5H, Harom),
5.94 (ddd, 1H, J1’–2’ = 5.8 Hz, J2’–3’cis = 11.1 Hz, J2’–3’trans = 16.4 Hz, H-2’), 5.29
(bd, 1H, J2’–3’trans = 16.6 Hz, H-3’), 5.19 (bd, 1H, J2’–3’cis = 10.9 Hz, H-3’), 4.54
(d, 1H, J1–2 = 9.2 Hz, H-1), 4.46 (dd, 1H, J1’a–2’ = 5.1 Hz, J1’a–1’b = 12.7 Hz, H-1’a),
4.24 (dd, 1H, J1’b–2’ = 5.9 Hz, J1’a–1’b = 12.7 Hz, H-1’b), 3.93 (dd, 1H, J6a-5 = 3.6 Hz,
J6a–6b = 11.8 Hz, H6a), 3.78 (dd, 1H, J6b-5 = 6.9 Hz, J6a–6b = 11.8 Hz, H6b), 3.52
(t, 1H, J3–4 = J2–3 = 9.0 Hz, H-3), 3.42 (t, 1H, J1–2 = J2–3 = 9.0 Hz, H-2), 3.41
(m, 1H, H5,), 3.35 (t, 1H, J3–4 = J4–5 = 8.7 Hz, H-4). 13C NMR (100 MHz, d-
MeOH): d(ppm) 139.6, 119.5, 92.2, 90.2, 84.8, 78.1, 76.6, 73.9, 65.6. MS (MALDI-
TOF): 335.7 (M + Na), 351.6 (M + K).
Anal. Calcd for C15H20O5S: C, 57.67; H, 6.45; S, 10.26. Found: C, 57.11; H, 6.78;
S, 10.48.
Phenyl 3-O-Allyl-4,6-p-methoxybenzyliden-1-thio-b-D-glucopyranoside (7). To
a stirred solution of compound 6 (3 g, 9.6 mmol) in dry MeCN (50 mL), anisaldehyde
dimethyl acetal (14.4 mmol, 2.45 mL) and a catalytic amount of p-TSA were added
under an argon atmosphere. The product precipitates immediately as a white solid from
the dark red solution. The mixture was stirred 30 min at rt, then cooled to 0°C for
30 min to promote the crystallisation of the product.
Pure compound 7 was recovered as white needles by filtration of the crude. The
mother liquors were concentrated and crystallization from cold acetonitrile was repeated
25°
to recover a second crop of the product (3.88 g in total, 94% yield). [a]D
+ 7.8 (c 1,

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D-Glucose as Scaffold
65
1
CHCl3). H NMR (300 MHz, CDCl3): d(ppm) 7.50–7.30 (m, 5H, Harom), 6.88 (m, 4H,
H
arom), 5.83 (ddd, 1H, J1’–2’ = 6.4 Hz, J2’–3’cis = 10.7 Hz, J2’–3’trans = 17.1 Hz, H-2’),
5.49 (s, 1H, HPMB), 5.28 (bd, 1H, J2’–3’trans = 17.1 Hz, H-3’), 5.19 (bd, 1H, J2’–3’cis
=
10.7 Hz, H-3’), 4.63 (d, 1H, J1–2 = 9.6 Hz, H-1), 4.40 (dd, 1H, J1’a–2’ = 6.2 Hz,
J1’a–1’b = 12.7 Hz, H-1’a), 4.35 (dd, 1H, J4–5 = 4.7, J3–4 = 9.9 Hz, H-4), 4.25 (dd,
1H, J1’b–2’ = 5.9 Hz, J1’a–1’b = 12.7 Hz, H-1’b), 3.80 (s, 3H, OCH3), 3.75 (t, 1H,
J3–4 = J2–3 = 9.9 Hz, H-3), 3.60–3.40 (m, 3H, H-2, H-5 and 2 H-6). 13C NMR
(100 MHz, CDCl3): d(ppm) 117.7, 113.8, 101.4, 88.7, 81.6, 81.3, 74.0, 72.4, 71.0,
68.8, 55.6. MS (MALDI-TOF): 454.3 (M + Na), 470.7 (M + K).
Anal. Calcd for C15H20O5S: C, 57.67; H, 6.45; S, 10.26. Found: C, 57.11; H, 6.78;
S, 10.48.
Phenyl 3-O-Allyl-4-p-methoxybenzyl-1-thio-b-D-glucopyranoside (1). To a
solution of compound 7 (0.81 g, 1.89 mmol) in dry CH2Cl2/Et2O (2:1, 15 mL), a
1 M solution of LiAlH4 in THF (8.7 mL, 8.7 mmol) was added under an argon
atmosphere and the mixture was refluxed for 4 h. After cooling the mixture to rt,
AlCl3 (1 g, 9.2 mmol) in dry Et2O (10 mL) was added dropwise and the solution
was then refluxed for a further 4 h. The crude was then diluted with AcOEt (50 mL)
and, after standard workup, pure compound 1 was recovered as a white solid (0.80 g,
98% yield).
1
[a]D25°(c 1, CHCl3) + 28.8. H NMR (300 MHz, CDCl3): d(ppm) 7.60–7.30 (m,
5H, Harom), 6.85–7.35 (m, 4H, Harom), 5.99 (ddd, 1H, J1’–2’ = 5.6 Hz, J2’–3’cis = 10.0
Hz, J2’–3’trans = 16.7 Hz, H-2’), 5.31 (bd, 1H, J2’–3’trans = 16.7 Hz, H-3’), 5.19 (bd, 1H,
J2’–3’cis = 10.0 Hz, H-3’), 4.66 (ABq, 2H, CH2–PMB), 4.52 (d, 1H, J1–2 = 8.2 Hz, H-
1), 4.43–4.30 (m, 2H, H-1’a, H-1’b), 3.82 (bd, 1H, H-6a), 3.80 (s, 3H, OCH3), 3.67 (bd,
1H, H-6b), 3.50–3.30 (m, 4H, H-2, H-3, H-4 and H-5). 13C NMR (100 MHz, CDCl3):
d(ppm) 117.3, 114.1, 88.4, 85.7, 79.8, 77.0, 75.0, 74.5, 73.0, 62.5, 55.6. MS (MALDI-
TOF): 455.3 (M + Na), 470.4 (M + K).
Anal. Calcd for C23H28O6S: C, 63.87; H, 6.52; S, 7.41. Found: C, 64.01; H, 6.58;
S, 7.48.
Phenyl 3-O-tbutyldimethylsilyl-4,6-p-methoxybenzylidene-1-thio-b-D-gluco-
pyranoside (9). To a solution of compound 8 (1 g, 2.56 mmol) in dry CH2Cl2
(20 mL), TBDMS chloride (0.57 g, 3.84 mmol) and imidazole (0.35 g, 5.12 mmol)
were added under an argon atmosphere and the mixture was refluxed for 24 h. After
dilution with AcOEt (50 mL), the crude was submitted to standard work-up and
purified by column FC (AcOEt/petroleum ether with 1% triethylamine), affording 9 as
a colorless oil (1.2 g, 94%). [a]D25°(c 1, CHCl3) + 22.8. 1H NMR (400 MHz,
CDCl3): d(ppm) 7.60–7.20 (m, 5H, Harom), 6.85 (m, 4H, Harom), 5.46 (s, 1H, HPMB),
4.64 (d, 1H, J1–2 = 9.8 Hz, H-1), 4.40 (dd, 1H, J1’a–2’ = 6.2 Hz, J1’a–1’b = 12.7 Hz,
H-1’a), 4.31 (dd, 1H, J4–5 = 4.7, J3–4 = 9.9 Hz, H-4), 4.25 (dd, 1H, J1’b–2’ = 5.9
Hz, J1’a–1’b = 12.7 Hz, H-1’b), 3.80 (s, 3H, OCH3), 3.75 (t, 1H, J3–4 = J2–3 = 9.9
Hz, H-3), 3.60–3.40 (m, 3H, H-2, H-5 and 2 H-6). 13C NMR (100 MHz, CDCl3):
d(ppm) 113.6, 101.8, 89.1, 81.1, 76.3, 73.9, 71.1, 68.9, 55.6, 26.2. MS (MALDI-
TOF): 527.6 (M + Na), 543.8 (M + K).
Anal. Calcd for C26H36O6SSi: C, 61.87; H, 7.19; S, 6.35; Si, 5.56. Found: C,
61.91; H, 7.58; S, 6.48; Si, 5.32.

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66
Peri et al.
Phenyl 2-O-Allyl-3-O-tert-butyldimethylsilyl-4,6-p-methoxybenzyliden-1-thio-b-
D-glucopyranoside (10). A vigorously stirred solution of compound 9 (500 mg,
1 mmol) in dry DMF (20 mL) was cooled to 0°C. Sodium hydride (80 mg of a 60%
suspension in oil, 2 mmol) and allyl bromide (170 mL, 2 mmol) were added
portionwise over 15 min, then the reaction mixture was allowed to warm to rt and
stirred at this temperature for 2 hrs. Methanol was carefully added to the mixture to
hydrolyze residual sodium hydride, and solvents were evaporated in vacuo. After usual
work-up and column chromatography (AcOEt/petroleum ether 0.5:9.5, 1% triethyla-
mine), compound 10 was recovered as a colorless oil (380 mg, 70%). [a]D25°(c 1,
1
CHCl3) + 17.3. H NMR (400 MHz, CDCl3): d(ppm) 7.40 (m, 5H, Harom), 6.85 (m,
4H, Harom), 5.98 (m, 1H, H-2’), 5.45 (s, 1H, HPMB), 5.31 (dd, 1H, J3’a–3’b = 17.2 Hz,
J3’a–2’ = 1.5 Hz, H-3’a), 5.19 (dd, 1H, J3’b–3’a = 10.4 Hz, J3’b–2’ = 1.4 Hz, H-3’b),
4.70 (d, 1H, J1–2 = 9.9 Hz, H-1), 4.39 (dd, 1H, J1’a–1’b = 11.4 Hz, J1’a–2 = 5.7 Hz,
H-1’a), 4.30 (m, 2H), 3.82 (s, 3H, OCH3), 3.82 (m, 1H), 3.73 (t, 1 H, J = 10.3 Hz),
3.45 (m, 2H), 3.27 (t, 1H, J = 9.8 Hz), 0.85 (s, 9H, HtBu), 0.22 (s, 1H, HMe), 0.00 (s,
3H, HMe). 13C NMR (100 MHz, CDCl3): d(ppm) 117.6, 113.6, 102.6, 88.9, 81.8, 81.5,
76.4, 75.0, 70.6, 68.9, 55.6, 26.2, À 3.7, À 4.0. MS (MALDI-TOF): 567.4 (M + Na),
583.6 (M + K).
Anal. Calcd for C29H40O6SSi: C, 63.94; H, 7.40; S, 5.89; Si, 5.16. Found: C,
63.71; H, 7.38; S, 5.58; Si, 5.12.
Phenyl-2-O-allyl-4-p-methoxybenzyl-1-thio-b-D-glucopyranoside (2). Com-
mpound 10 (540 mg, 1 mmol), was reacted according to the same procedure used to
transform 7 in 1. After usual workup, pure compound 2 was recovered as a white solid
(0.80 g, 98% yield). [a]D25°(c.1, CHCl3) + 34.2. H NMR (300 MHz, CDCl3): d(ppm)
1
7.60–7.30 (m, 5H, Harom), 6.85–7.35 (m, 4H, Harom), 5.98 (ddd, 1H, J1’–2’ = 5.8 Hz,
J2’–3’cis = 10.8 Hz, J2’–3’trans = 17.7 Hz, H-2’), 5.31 (bd, 1H, J2’–3’trans = 17.7 Hz, H-
3’a), 5.21 (bd, 1H, J2’–3’cis = 10.9 Hz, H-3’b), 4.70 (ABq, 2H, CH2–PMB), 4.62 (d, 1H,
J1–2 = 9.7 Hz, H-1), 4.41 (dd, 1H, J = 11.7, 5.8 Hz, H-1’a), 4.23 (dd, 1H, J = 12.6,
5.8 Hz, H-1’b), 3.90–3.60 (m, 3H, H-6a, H-6b, H-3), 3.78 (s, 3H, OCH3), 3.43 (t, 1H,
H-4, J = 9.2 Hz), 3.35 (m, 1H, H-5), 3.22 (t, 1H, H-2, J = 9.2 Hz). 13C NMR (100
MHz, CDCl3): d(ppm) 118.0, 114.1, 87.3, 80.9, 79.3, 78.7, 77.1, 74.6, 74.4, 62.6, 55.6.
MS (MALDI-TOF): 456.6 (M + Na + H), 472.4 (M + K + H).
Anal. Calcd for C23H28O6S: C, 63.87; H, 6.52; S, 7.41. Found: C, 64.01; H, 6.58;
S, 7.48.
Loading of 1 and 2 onto solid supports. The direct attachment of 1 and 2 to
carboxy-polystyrene resin was carried out according to the following procedure.
Tentagel carboxy resin (Novabiochem, 0.27 mmol/g, 0.4 g, 0.10 mmol) was allowed to
swell by shaking for 30 min in CH2Cl2 (5 mL), then was shaken for 30 min in dry THF
(5 mL) to remove moisture. Compound 1 (232 mg, 0.54 mmol), DIC (83 mL, 0.54
mmol), HOBt (4 mg, 0.02 mmol), DMAP (2.5 mg, 0.02 mmol) and pyridine (43 mL,
0.54 mmol) were dissolved under an argon atmosphere in dry DMF (4 mL) and the
mixture was added to the resin. The suspension was shaken under an argon atmosphere
for 72 h, then solvents and reactants were removed by filtration and the resin was
washed with CH2Cl2 (5 mL, 30 min  2), acetone (5 mL, 30 min  2), MeOH (5 mL,
30 min  2) and CH2Cl2 (5 mL, 30 min  2) and finally dried in vacuo for 12 h.

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D-Glucose as Scaffold
67
In order to determine the loading, 200.5 mg of resin were suspended in dioxane
(1 mL) and aqueous 2% NaOH (1.5 mL) and shaken for 24 h at rt. The solvents were
filtered and the resin was washed with Et2O (5 mL, 30 min  2), water (5 mL, 30
min  2) and Et2O (5 mL, 30 min  2) collecting all the effluents. HCl 0.1 N was
added under stirring until pH 5 was reached. The product was extracted with AcOEt
(3 Â 10 mL). The organic phase was dried over sodium sulfate, filtered and the solvents
evaporated in vacuo; 17.5 mg of pure 1 were recovered, corresponding to a loading of
0.2 mmol/g. Compound 2 was loaded using an identical procedure and gave similar
loading values.
The loading of 1 and 2 to amino polystyrene HL resin was performed by reacting
the sugars previously functionalised with a succinate linker on C-6 with resin. To a
solution of sugar 1 (100 mg, 0.232 mmol) in dry CH2Cl2 (1.5 mL), succinic anhydride
(46 mg, 0.46 mmol), dry pyridine (56 mL, 0.696 mmol) and DMAP (catalytic amount)
were added under an argon atmosphere and the reaction mixture was cooled to 0°C.
After 30 min at 0°C, EtOH (3 mL) was added and the reaction mixture was stirred for
15 min at rt to eliminate the excess anhydride. Then the solvents were evaporated and
the product purified by FC (eluent: AcOEt/CHCl3 1:1). Pure C-6 succinate derivative
was obtained as a white solid (104 mg, 85% yield).
To a solution of C-6 succinate derivative (232 mg, 0.44 mmol) in dry DMF
(1.5 mL), HBTU (159 mg, 0.418 mmol), HOBt (65 mg, 0.44 mmol) and DIPEA (112
mL, 0.66 mmol) were added and the mixture was stirred at rt for 10 min. Then this
solution was transferred into a solid phase reactor in which aminomethylated poly-
styrene HL resin (100 mg, 0.11 mmol) was previously swelled in dry CH2Cl2. The
suspension was shaken at rt for 1 h, then the resin was drained and washed with DMF
(2 mL, 30 min  2), THF (2 mL, 30 min  2) and CH2Cl2 (2 mL, 30 min  2). In
order to determine the loading gravimetrically the resin was suspended in dioxane (1 mL)
and aqueous 2% NaOH (1.5 mL) and shaken overnight at rt. The mixture was filtered and
the resin was washed with Et2O (2 mL, 30 min  2), water (2 mL, 30 min  2) and Et2O
(2 mL, 30 min  2) collecting all the effluents. HCl (0.1 N) was added under stirring
until pH 5 was reached. The mixture was extracted with AcOEt (3 Â 2 mL). Pure
compound 1 was recovered (39 mg, corresponding to a loading of 0.9 mmol/g).
Phenyl 3-O-allyl-6-benzamidosuccinyl-4-p-methoxybenzyl-1-thio-b-D-glucopy-
ranoside (3). Compound 1 was converted into the corresponding C-6 succinic ester
derivative as described in the previous section. To a solution of C-6 succinic ester
derivative (500 mg, 0.94 mmol) in dry DMF (10 mL), benzylamine (123 mL, 1.13
mmol), HBTU (430 mg, 1.13 mmol) and DIPEA (390 mL, 2.26 mmol) were added
under an argon atmosphere and the reaction mixture was stirred at rt for 2 h.
After this time, the solvent was evaporated, the residue dissolved in AcOEt and
the organic layer washed with water, aqueous HCl (0.1 N), aqueous NaHCO3 and
water. After usual work-up, the product was purified by FC (eluent: AcOEt/petroleum
ether 7:3). Pure compound 3 was obtained as a colourless oil (553 mg, 95% yield).
1
[a]D25°(c 1, CHCl3) + 12.7. H NMR (400 MHz, CDCl3): d(ppm) 7.40–7.20 (m, 5 H,
H
arom), 7.35–6.85 (4H, Harom), 5.95 (m, 2H, H-2’, NH), 5.32 (dd, 1H, J = 17.0, 1.5
Hz, H-3’a), 5.19 (bd, 1H, J = 11.5 Hz, H-3’b), 4.63 (ABq, 2H, CH2–PMB), 4.45–
4.30 (m, 6H, H-1, H-6a, 2 Ph–CH2–NH, 2 H-1’), 4.19 (dd, 1H, J = 11.7, 5.3 Hz, H-6b),
3.78 (s, 3H, OCH3), 3.50–3.30 (m, 4H, H-2, H-3, H-4, H-5), 2.65 (m, 2H, CO–CH2), 2.45

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68
Peri et al.
(m, 2H, CO–CH2). 13C NMR (100 MHz, CDCl3): d(ppm) 172.4, 171.1, 117.4, 114.1,
88.2, 85.8, 77.3, 76.7, 74.9, 74.5, 72.7, 63.6, 55.6, 40.0, 31.4, 30.0. MS (MALDI-TOF):
642.7 (M + Na), 658.7 (M + K).
3-O-Allyl-6-benzamidosuccinyl-4-p-methoxybenzyl-b-D-glucopyranosyl sulfox-
ide (3a). To a solution of compound 3 (500 mg, 0.81 mmol) in dry CH2Cl2 (5 mL)
cooled at À 78°C, m-CPBA (123 mL, 1.13 mmol) dissolved in dry CH2Cl2 (5 mL) was
added and the mixture was stirred at this temperature, and TLC (AcOEt/petroleum
ether, 6:4) was used to monitor the reaction. Upon completion, a saturated aqueous
solution of FeSO4 (20 mL) was added, the organic layer was diluted with CH2Cl2
(10 mL) and the biphasic mixture vigorously stirred at rt for 10 min. After usual
workup, the product was purified by FC (eluent: AcOEt/petroleum ether 7:3). Pure
compound 3a was obtained as a mixture of diastereomers 3a’ and 3a@ in almost
equimolar amounts (colourless oil, 343 mg, 82% yield). 3a’: [a]D25°(c 0.1,
CHCl3) + 35.5. 1H NMR (400 MHz, CDCl3): d(ppm) 8.0–7.0 (m, 14 H, Harom),
6.12 (bt, 1H, NH), 6.01 (m, 1H, H-2’), 5.33 (dd, 1H, J = 17.1, 1.5 Hz, H-3’a), 5.20 (dd,
1H, J = 10.4, 1.2 Hz, H-3’b), 4.63 (ABq, 2H, CH2–PMB), 4.55–4.40 (m, 3H, H-1’a,
Ph–CH2–NH), 4.34 (m, 2 H, H-6a and H-1’b), 4.20 (t, 1H, J1–2 = 9.5 Hz, H-2), 4.12
(dd, 1H, J6a–6b = 11.9 Hz, J5–6b = 5.4 Hz, H-6b), 3.95 (d, 1H, J = 9.5 Hz, H-1), 3.79
(s, 3H, OCH3), 3.49 (t, 1H, J = 8.6 Hz, H-3), 3.41 (t, 1H, J = 8.6 Hz, H-4), 3.37 (m,
1H, H-5), 2.69 (m, 2H, COCH2), 2.52 (m, 2H, COCH2). 13C NMR (100 MHz, CDCl3):
d(ppm) 172.5, 171.3, 117.3, 114.1, 93.0, 85.3, 77.7, 75.7, 75.1, 74.7, 73.9, 63.1, 55.6,
44.1, 31.3, 29.8. MS (MALDI-TOF): 661.2 (M + Na), 677.4 (M + K). (M + K).
Anal. Calcd for C34H39NO9S: C, 64.03; H, 6.16; S, 5.03. Found: C, 64.09; H, 6.77;
S, 4.98.
1
3a@: [a]D25°(c 0.1, CHCl3) + 25.6. H NMR (400 MHz, CDCl3): d(ppm) 8.0–7.0
(m, 14 H, Harom), 6.08 (bt, 1H, NH), 5.97 (m, 1H, H-2’), 5.32 (dd, 1H, J = 17.2, 1.4
Hz, H-3’a), 5.20 (dd, 1H, J = 10.5, 1.4 Hz, H-3’b), 4.59 (ABq, 2H, CH2–PMB), 4.50–
4.40 (m, 3H, Ph–CH2–NH, H-1’a), 4.30 (m, 2 H, H-6a, H-1’b), 4.09 (dd, 1H, J6a–
= 11.9 Hz, J5–6b = 4.8 Hz, H-6b), 3.83 (t, 1H, J = 8.7 Hz, H-2), 3.79 (m, 4H, H-1
6b
and OCH3), 3.53 (t, 1H, J = 8.8 Hz, H-3), 3.45 (m, 1H, H-5), 3.18 (t, 1H, J = 9.4 Hz,
H-4), 2.59 (m, 2H, COCH2), 2.48 (m, 2H, COCH2). 13C NMR (100 MHz, CDCl3):
d(ppm) 172.4, 171.1, 117.5, 114.1, 88.4, 85.7, 77.9, 75.6, 75.0, 74.8, 71.01, 62.7, 55.6,
44.1, 31.3, 29.7. MS (MALDI-TOF): 661.5 (M + Na), 677.4 (M + K).
Anal. Calcd for C31H35NO8S: C, 64.01; H, 6.06; S, 5.51. Found: C, 64.18; H, 6.08;
S, 5.53.
Phenyl 3-O-allyl-6-benzamidosuccinyl-1-thio-b-D-glucopyranoside (3b).
A
solution of compound 3 (100 mg, 0.16 mmol) in TFA/CH2Cl2 (1:1) was stirred 1 h
at rt until the hydrolysis was complete. Solvents were evaporated and crude purified by
flash chromatography (AcOEt/petroleum ether, 4:6). Pure compound 3b was recovered
1
as a colorless oil (73.6 mg, 92% yield). [a]D25°(c 0.1, CHCl3) À 18.5. H-NMR (400
MHz, CDCl3): d(ppm) 7.5–7.2 (m, 14 H, Harom), 6.20 (bt, 1H, NH), 5.95 (m, 1H, H-
2’), 5.35 (dd, 1H, J = 17.5, 1.3 Hz, H-3’a), 5.15 (dd, 1H, J = 10.7, 1.6 Hz, H-3’b),
4.45 (ABq, 2H, Ph–CH2–NH), 4.40–4.20 (m, 3H, H-1’a, H-1, 2 H-6), 4.10 (m, 1H,

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D-Glucose as Scaffold
69
H1’b), 3.50 (m, 2H, H-2 and H-4), 3.39 (t, 1H, J = 9.0 Hz, H-3), 3.35 (m, 1H, H-5),
2.80 (bs, 1H, OH), 2.70 (m, 2H, COCH2), 2.50 (m, 2H, COCH2). 13C NMR (100 MHz,
CDCl3): d(ppm) 173.1, 171.5, 117.6, 88.5, 85.0, 77.9, 74.2, 72.4, 69.7, 63.9, 44.1, 31.3,
30.1, 29.9. MS (MALDI-TOF): 524.5 (M + Na), 540.6 (M + K).
Anal. Calcd for C26H31NO7S: C, 62.26; H, 6.23; S, 6.39. Found: C, 62.29; H, 6.34;
S, 6.23.
Phenyl 6-benzamidosuccinyl-4-p-methoxybenzyl-1-thio-b-D-glucopyranoside
(3c). To a solution of 3 (100 mg, 0.16 mmol) in dry THF (5 mL), degassed with
several vacuum/argon cycles, Ir[COD(PPh2Me2)2]PF6 was added in catalytic amount and
the solution turned to a light red color. Then the suspension was treated with cycles of
vacuum/hydrogen and turned to a pale yellow color, indicating the formation of
IrH2[COD(PPh2Me2)2]PF6. The suspension was then stirred for 24 h at rt. After this time,
p-TsOH (catalytic) dissolved in MeOH/dioxane (1:9, 5 mL), was added and the solution
was stirred 24 h at rt. Solvents were evaporated and crude purified by flash chro-
matography (AcOEt/petroleum ether, 3:7). Pure compound 3c was recovered as a
colorless oil (60 mg, 65% yield). [a]D25°(c 0.1, CHCl3) + 12.5. H NMR (400 MHz,
1
CDCl3): d(ppm) 7.40–7.20 (m, 5 H, Harom), 7.30–6.90 (4H, Harom), 5.97 (bs, 1H, NH),
4.65 (ABq, 2H, CH2–PMB), 4.50–4.35 (m, 5H, H-6a, 2 Ph–CH2–NH, 2 H-1’), 4.23 (dd,
1H, J = 11.4, 4.7 Hz, H-6b), 3.78 (m, 4H, H-1 and OCH3), 3.53 (t, 1H, J = 8.7 Hz, H-
2), 3.30 (m, 3H, H-3, H-4, H-5), 2.74 (m, 2H, CO–CH2), 2.51 (m, 2H, CO–CH2). 13C
NMR (100 MHz, CDCl3): d(ppm) 172.4, 171.1, 117.4, 87.11, 84.5, 79.3, 77.4, 75.6, 74.5,
72.7, 63.6, 55.6, 40.0, 30.7, 29.4. MS (MALDI-TOF): 604.7 (M + Na), 620.5 (M + K).
Anal. Calcd for C31H35NO8S: C, 64.01; H, 6.06; N, 2.41; S, 5.51. Found: C, 64.29;
H, 6.04; S, 5.23.
Phenyl 3-O-allyl-4-p-methoxybenzyl-3-benzyloxymethyl-1-thio-b-D-glucopy-
ranoside (11). To a suspension of Tentagel resins 2a (0.15 mmol) in dry DMF
(2 mL), benzyloxymethyl chloride (200 mL, 1.5 mmol, CAUTION: toxic, carcinogenic),
DIPEA (384 mL, 2.25 mmol) and TBAI (110 mg, 0.30 mmol) were added under argon
atmosphere and the mixture was shaken 4 h at rt. Resin was then drained, washed with
CH2Cl2 (2 Â 2 mL), THF (2 Â 2 mL), CH2Cl2 (2 Â 2 mL) and product cleaved by
suspending the resin in dioxane (1 mL) and aqueous 2% NaOH (1.5 mL) and shaking
overnight at rt. After usual washings of the resin and workup, crude was purified by
flash chromatography (AcOEt/petroleum ether, 1:9) affording pure compound 11 as a
1
colourless oil (82 mg, 98% yield). [a]D25°(c 0.1, CHCl3) + 23.4. H NMR (400 MHz,
CDCl3): d(ppm) 7.30 (m, 10H, Harom), 7.0 (AXq, 4H, Harom), 5.99 (m, 1H, H-2’), 5.27
(dd, 1H, J = 15.8, 1.8 Hz, H-3’a), 5.17 (bd, 1H, J = 11.2 Hz, H-3’b), 5.03 (s, 1H, O–
CH2–O), 4.80–4.60 (2ABq, 4H, CH2–PMB and O–CH2–Ph), 4.62 (d, 1H, J = 9.6
Hz, H-1), 4.40 (dd, 1H, J = 12.5, 5.8 Hz, H-1’a), 4.26 (dd, 1H, J = 11.7, 5.8 Hz,
H-1’b), 3.82 (dd, 1H, J = 11.8, 2.8 Hz, H-6a), 3.79 (t, 1H, J = 8.8 Hz, H-3), 3.77
(s, 1H, OCH3), 3.64 (dd, 1H, J = 11.9, 4.8 Hz, H-6b), 3.49 (t, 1H, J = 9.6 Hz),
3.35 (m, 1H, H-5), 3.32 (t, 1H, J = 9.1 Hz, H-2). MS (MALDI-TOF): 575.7
(M + Na), 591.2 (M + K).
Anal. Calcd for C31H36O7S: C, 67.37; H, 6.57; S, 5.80. Found: C, 67.29; H, 6.54;
S, 5.73.

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70
Peri et al.
ABBREVIATIONS
m-chloroperbenzoic acid
dichlorodicyanoquinone
2,6-di-tert-butyl-4-methylpyridine
diisopropylcarbodiimide
diisopropylethylamine
N,N-dimethyl-4-aminopyridine
dimethylformamide
flash chromatography
O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium hexafluorophos-
phate
N-hydroxybenzotriazole
m-CPBA
DDQ
DBMP
DIC
DIPEA
DMAP
DMF
FC
HBTU
HOBt
NIS
PMB
N-iodosuccinimide
p-methoxybenzyl
PS/DV
TBDMS
TFA
polystyrene/divinylbenzene (resin)
tert-butyldimethylsilyl
trifluoroacetic acid
TIS
p-TSA
TMSOTf
tris-isopropylsilane
p-toluenesulfonic acid
trimethylsilyl trifluoromethanesulfonate
ACKNOWLEDGMENTS
We gratefully acknowledge Raffaella Rossini, Stefano Vignando and Ilaria Fossati
for their contribution to the experimental work and GlaxoSmithKline and MIUR for
financial support.
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Received May 9, 2002
Accepted December 3, 2002