Solution synthesis of two orthogonally protected lactosides as tetravalent disaccharide-based scaffolds

Article abstract of DOI:10.1002/ejoc.200300807

Two tetravalent lactosidic scaffolds have been synthesised in solution from commercial lactose. Careful manipulation of the protecting groups allowed us to orthogonally protect four OH groups for their use as diversity sites for the development of broad screening libraries of sugar mimics. The selective access to each of these hydroxy groups has been demonstrated on scaffold 2 by deprotection and functionalisation with p-fluorophenyl isocyanate. Finally, the 6-OH derivative of compound 2 was covalently attached to a polymeric support. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300807

FULL PAPER
Solution Synthesis of Two Orthogonally Protected Lactosides as Tetravalent
Disaccharide-Based Scaffolds
Sergio Castoldi,[a] Massimiliano Cravini,[a] Fabrizio Micheli,[b] Elisabetta Piga,[b]
Giovanni Russo,[a,c] Pierfausto Seneci,[a] and Luigi Lay*[a]
Keywords: Carbohydrate scaffolds / Lactose / Protecting groups / Solid phase synthesis
Two tetravalent lactosidic scaffolds have been synthesised in
solution from commercial lactose. Careful manipulation of
the protecting groups allowed us to orthogonally protect four
OH groups for their use as diversity sites for the development
of broad screening libraries of sugar mimics. The selective
strated on scaffold 2 by deprotection and functionalisation
with p-fluorophenyl isocyanate. Finally, the 6-OH derivative
of compound 2 was covalently attached to a polymeric sup-
port.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
access to each of these hydroxy groups has been demon- Germany, 2004)
Introduction
based libraries,[7] the existing techniques are still inadequate
for reproducing the enormous structural and functional di-
versity of natural carbohydrates. Sugar mimics that are en-
dowed with very similar biological properties, but are struc-
turally and synthetically simpler than their natural counter-
parts, could offer a valuable alternative. One option that
skips the difficulties often related to the stereocontrol of the
glycosylation is to generate libraries of carbohydrate mi-
metics by sequential and regioselective addition of simple
sugar analogues to a multifunctionalised, preformed, poly-
mer-bound saccharidic scaffold. The decoration of the scaf-
fold could be addressed by replacing the glycosylation steps
with simple and reliable reactions of classical organic syn-
thesis. Moreover, this strategy exploits the advantages of
solid phase synthesis in terms of its speed, efficiency, and
the elimination of tedious workup and purification steps.
Careful examination of the structures of complex oligo-
saccharides endowed with biological activity reveals they
can often be envisaged as a sequence of blocks assembled
in different ways. Examples include both free carbohydrates,
such as human milk oligosaccharides, which exhibit antiad-
hesive properties and inhibitory activity towards many
pathogens and protect breast-fed infants against infections
during the lactation period,[8,9] and important glycoconju-
gates, such as glycoproteins and various glycolipids. In these
compounds, each block is composed of a disaccharidic core
with various branches (when present) such as fucose or
sialic acid. Typical core structures widely occurring in com-
plex oligosaccharides are Galβ(1Ǟ4)GlcNAc (lactosam-
ine), Galβ(1Ǟ3)GlcNAc and Galβ(1Ǟ4)Glc (lactose). In
principle, the application of the above strategy can lead to
a library of sugar analogues by decorating a scaffold corre-
sponding to one of the disaccharidic core structures with
The fundamental role played by carbohydrates in many
cellular recognition phenomena is now well established.[1]
Carbohydrates are primarily involved in inflammatory pro-
cesses, bacterial and viral invasions, tumour growth and
metastasis, and many other crucial biological events. Be-
cause of their biological importance and unique chemical
features, the synthetic community’s interest in these mol-
ecules has been raised during last few years: tailor-made
sugar-based compounds that are able to interfere in key
biological mechanisms would represent a powerful weapons
in biomedicine. Therefore, the generation of carbohydrate
libraries is a highly attractive goal toward adequately ex-
ploiting the broad potential envisioned for saccharide-based
drugs. To address this issue, combinatorial chemistry tech-
nologies, both in solution and in solid phases,[2Ϫ5] should
be extremely advantageous, but the application of these
techniques to the synthesis of oligosaccharides and glyco-
conjugates has been hampered largely by the typical chal-
lenges associated with classical carbohydrate synthesis,[6]
such as laborious protecting group manipulations and the
lack of a general method for the stereoselective formation
of glycosidic linkages. Although significant developments in
solid phase oligosaccharide synthesis have been disclosed
recently to allow the preparation of a number of sugar-
[a]
Dipartimento di Chimica Organica
e Industriale, Centro
Interdisciplinare Studi bio-molecolari e applicazioni Industriali
`
(CISI), Universita degli Studi di Milano,
Via G. Venezian 21, 20133 Milano, Italy
Fax: (internat.) ϩ 39-02-50314061
GlaxoSmithKline, Medicine Research Centre,
Via A. Fleming 4, 37135 Verona, Italy
CNR (Istituto di Scienze e Tecnologie Molecolari),
Via G. Venezian 21, 20133 Milano, Italy
[b]
[c]
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DOI: 10.1002/ejoc.200300807
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S. Castoldi, M. Cravini, F. Micheli, E. Piga, G. Russo, P. Seneci, L. Lay
FULL PAPER
simple blocks mimicking the branches occurring in the and thexyldimethylsilyl (TDS) ether units as orthogonally
natural molecule. cleavable protecting groups and benzyl (Bn) ether and
The use of carbohydrates, especially monosaccharides, as benzylidene acetal moieties as permanent protecting
molecular scaffolds for the synthesis of combinatorial li- groups.
braries has already been described.[10Ϫ18] Monosaccharides
In the first part of our endeavour, we faced the solution
possess a unique set of chemical and structural features that phase synthesis of scaffold 1 (Figure 1), in which the 6-, 3-,
make them particularly attractive for this task. They are 2Ј- and 3Ј-OH groups are orthogonally protected. Actually,
readily available in a variety of diastereoisomeric forms, as we detail below, an unexpected migration led to the
they are chiral and conformationally rigid molecules pro- alternative scaffold 2 (Figure 1), which contains 6-, 2-, 2Ј-
viding a well-defined three-dimensional spatial arrangement and 3Ј-hydroxy groups as diversity sites.
of substituents, and they possess up to five hydroxy groups
The 6-O-TDS group has a twofold role. First, it can be a
for chemical modification. Taken together, these features fourth diversification site for the solution phase synthesis
suggest that monosaccharides are privileged platforms with of libraries from scaffold 2. In addition, it mimics the at-
which to design primary screening libraries for drug dis- tachment of the scaffold to the polymeric support through
covery.[19,20] Additional advantages derive from the ability a silyl ethereal linkage, which allows us to validate the suit-
of disaccharidic scaffolds to mimic or inhibit macromolecu- ability of our strategy for its application in solid phase syn-
lar interactions where potential pharmacophoric recog- thesis. Moreover, when using a solid phase protocol, the 6-
nition sites are spatially far apart. To the best of our knowl- OH group eventually can be functionalised, once the decor-
edge, however, very few examples of the syntheses and ap- ated scaffold has been cleaved from the polymer. Target 2
plications of disaccharidic scaffolds have been reported in was obtained according to Schemes 1 and 2.
the literature.[11,21,22] Lactose, which is available in large
Peracetylated lactose 4[23] was first converted into the
quantities as a by-product from dairies, is one of the cheap- methyl orthoester 5 in two steps[24] (Scheme 1, 84% overall
´
est disaccharides available on the market and one of the yield). After Zemplen deacetylation, compound 6 was 3Ј-O-
most diffused in nature. Therefore, we selected lactose as a allylated regioselectively by exploiting the stannylene acetal
template to generate a disaccharidic scaffold. Herein, we procedure, giving 7 in 87% overall yield. The regioselective
describe the solution synthesis of orthogonally protected opening of the orthoester ring with benzyl alcohol was par-
tetravalent lactosidic scaffolds 2 and 3 (Figure 1). The re- ticularly challenging. After many attempts, the best con-
gioselective deprotection/functionalisation of template 2 ditions we found were those in which trifluoromethanesul-
and its covalent attachment to a polymeric support, namely
butyl diethylsilane polystyrene (PS-DES) resin, is also re-
ported.
Figure 1. Structures of lactosidic scaffolds 1Ϫ3
Results and Discussion
The key to developing chemical diversity using carbo-
hydrate scaffolds is to find a strategy that allows chemical
differentiation of the hydroxy groups on the sugar nu-
cleus.[5,12,13] To address this issue, our approach towards
lactosidic scaffolds required the installation of two distinct
sets of protecting groups. A first set of orthogonal protect-
ing groups must be introduced on those hydroxy groups
selected as diversification sites to allow their selective de-
protection/functionalisation. The second set includes all the
other protecting groups that must remain unaffected during
the subsequent manipulations of the scaffold and are
eventually removed, possibly in a single step. We employed
Scheme 1. Synthesis of compounds 10α and 10β. Reagents and con-
ditions: a) MeONa, MeOH; b) Bu2SnϭO, MeOH reflux, AllBr,
˚
TBAI, toluene, 60 °C, 87% from 5; c) BnOH, TfOH, CH3CN, 3-A
molecular sieves, 0 °C, 70%; d) PhCH(OMe)2, CSA, CH3CN; e)
benzoyl ester (Bz) and p-methoxybenzyl (PMB), allyl (All) TBSOTf, collidine, DMF, 0 °C, 58% from 8 [α/β ϭ 2:5]
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Solution Synthesis of Two Orthogonally Protected Lactosides
FULL PAPER
fonic acid (TfOH) was used as an acidic promoter, produc- the 3-O-benzylated compound 13 was obtained; it derived
ing benzyllactoside 8 in 70% yield as a 2:5 α/β mixture, as from a surprisingly clean migration of the TBS group from
evidenced by NMR spectroscopy.
the 3-OH to the 2-OH group during the benzylation step.
Since the high polarity of compounds 8α/8β hampered Such base-promoted intramolecular migrations of silyl
their efficient chromatographic purification, we postponed groups have been reported previously.[25Ϫ31] Full desilyl-
the separation of the anomeric mixture to a later stage of ation of 13 (Ǟ 14) using tetrabutylammonium fluoride
the synthesis. The subsequent introduction of the 4Ј,6Ј-O- (TBAF) in THF, followed by regioselective 6-O-silylation
benzylidene acetal was therefore carried out on the 8α/8β with thexyldimethylsilyl chloride (TDSCl) and imidazole,
mixture to give compound 9 (α/β mixture). Next, silylation provided diol 15 (53% from 13).
of the remaining free hydroxy groups (3, 6 and 2Ј) furnished
Monobenzoylation of 15 was carried out by using a
the fully protected lactosidic intermediate 10 (α/β mixture) combination of benzoyl cyanide and triethylamine in
in 58% overall yield from 8. The separation of the anomers acetonitrile at Ϫ40 °C to afford compound 16.[32] Careful
was accomplished on compound 10, and gave 42% of 10β analysis of the NMR spectra of alcohol 16, in particular
together with 16% of 10α. The complete structure of both the low-field shift of H-2 (δ ϭ 5.28 ppm), allowed us to
isomers was determined by NMR spectroscopy: in particu- unambiguously assign the structure of compound 16 and
lar, 10β showed H-1 at δ ϭ 5.12 ppm (J1,2 ϭ 8.1 Hz), confirm that migration of the TBS group had occurred. The
whereas 10α exhibited H-1 at δ ϭ 5.08 ppm (J1,2 ϭ 3.8 Hz). possibility that such a migration occurred during the pre-
We decided to pursue our synthesis towards scaffold 2 using ceding saponification step was ruled out by submitting
the major anomer, 10β. Nevertheless, as we describe below, compound 11 to standard acetylation (Ac2O, py): only in-
anomer 10α turned out to be a useful intermediate for the termediate 10β was obtained (Scheme 2).
construction of a second lactosidic scaffold (compound 3,
Figure 1).
Having proved the correct structure of intermediate 16,
the last free 2Ј-OH group was alkylated using p-meth-
Differentiation of the remaining 6-, 2-, 3- and 2Ј-O atoms oxybenzyl chloride (PMBCl) in the presence of NaH and
units on 10β was achieved as outlined in Scheme 2. The 2- KI at Ϫ30 °C, providing the fully protected lactosidic scaf-
´
O-acetyl group of 10β was unaffected under Zemplen con- fold 2 in fair yield (51%). All attempts to improve the yield
ditions, but saponification with 0.15  NaOH in EtOH gave (e.g., increasing the temperature or extending the reaction
the alcohol 11, which was submitted directly to the benzyl- time) led to partial decomposition of 16. Nevertheless, this
ation step under Williamson conditions. We expected the step did not cause any loss of precious compound, since the
formation of the 2-O-benzylated compound 12. In contrast, unchanged starting material could be recovered and re-
as it became clear a few steps later with compound 16, only cycled.
Scheme 2. Synthesis of scaffold 2. Reagents and conditions: a) NaOH, EtOH, 40 °C; b) BnBr, NaH, DMF, 81% from 10β; c) TBAF,
THF, Ϫ30 °C; d) TDSCl, imidazole, DMF, 0 °C, 53% from 13; e) BzCN, Et3N, CH3CN, Ϫ40 °C, 50%; f) PMBCl, NaH, KI, DMF,
Ϫ30 °C, 51%
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With the protected scaffold 2 in our hands, we wanted to
validate our synthetic strategy by demonstrating that selec-
tive access to each of the orthogonally protected hydroxy
groups is indeed feasible.
Oxidative removal of the p-methoxybenzyl ether from
scaffold 2 occurred smoothly by employing 1,2-dichloro-
4,5-dicyanobenzoquinone (DDQ) to furnish alcohol 16
(Scheme 3). The newly liberated 2Ј-OH group was func-
tionalised by a reaction with p-fluorophenyl isocyanate in
the presence of triethylamine to afford carbamate 17 in an
unoptimised yield of 60% from scaffold 2. Deallylation was
achieved by treating 2 with PdCl2 and gave alcohol 18,
which was carbamoylated with p-fluorophenyl isocyanate to
produce compound 19 in an unoptimised yield of 52% from
2. Finally, 2-O-debenzoylation of 2 using 0.15  NaOH in
EtOH generated alcohol 20 in almost quantitative yield; 20
was converted into the corresponding p-fluorophenyl carba-
mate 21 in an unoptimised yield of 90% from scaffold 2.
Scheme 4. Synthesis of scaffold 3. Reagents and conditions: a)
NaOH, EtOH, 40 °C; b) TBAF, THF, Ϫ30 °C; c) TDSCl, imidaz-
ole, DMF, 0 °C, 57% from 10α; d) Bu2SnϭO, MeOH reflux, BnBr,
TBAI, toluene, 60 °C, 88%; e) BzCN, Et3N, CH3CN, Ϫ5 °C, 65%;
f) PMBCl, NaH, KI, DMF, Ϫ30 °C, 48%
Taking advantage of the stannylene acetal procedure, a
benzyl group was installed regioselectively on the 2-OH unit
to produce diol 26 in 88% yield. Monobenzoylation of 26
with benzoyl cyanide proceeded smoothly at Ϫ5 °C to pro-
vide the alcohol 27 in 65% yield. The structure of 27 was
readily confirmed from the 1H NMR spectroscopic data
(H-2Ј: δ ϭ 5.60 ppm). We note that the regioselectivity of
the benzoylation on diol 26 changed from that previously
described for diol 15. In the latter case (2,2Ј-diol), the ben-
zoyl ester was introduced on the 2-OH group, whilst the
3,2Ј-diol 26 showed a marked preference for 2Ј-O-acylation,
as has reported previously for similar compounds.[32] The
synthesis of scaffold 3 was then completed by p-methoxy-
benzylation of the remaining 3-OH group.
As a last stage of our endeavour, the alcohol 22 was anch-
ored to PS-DES resin through its 6-OH group to afford a
polymer-bound lactosidic template that is suitable for the
solid phase generation of lactose-based libraries for broad
screening and for decoration at the 2-, 2Ј- and 3Ј-positions.
PS-DES resin required prior activation by treating it with
Scheme 3. Selective access to orthogonally protected OH groups.
Reagents and conditions: a) DDQ, CH2Cl2; H2O; b) p-FPhNCO,
Et3N, CH2Cl2: 17 (60%), 19 (52%), 21 (90%) from 2; c) PdCl2,
AcONa, AcOH/H2O; d) NaOH, EtOH; e) TBAF, THF, Ϫ30 °C,
87%
Selective removal of the TDS group was also ac-
complished to prove the feasibility of an nondestructive 1,3-dichloro-5,5-dimethylhydantoin (28) to convert the
cleavage of scaffold 2 from a PS-DES resin featuring silyl- SiϪH bonds into SiϪCl bonds (Scheme 5).[33]
ated linkers. The treatment of lactoside 2 with TBAF in
THF afforded compound 22 in 87% yield (Scheme 3).
Next, the activated polymer 29 was reacted with alcohol
22 in CH2Cl2 in the presence of imidazole under strictly dry
Synthesis of scaffold 3, which allows selective access to conditions. The resin-bound scaffold 30 was recovered by
6-, 3-, 2Ј- and 3Ј-hydroxy groups, is outlined in Scheme 4. filtration and washed with DMF, DMF/H2O (1:1), THF/
Compound 10α was deacetylated as described previously H2O (1:1) and THF. Analysis by diffusive reflectance infra-
for 10β to give alcohol 23. Desilylation (TBAF, Ϫ30 °C to red Fourier transform (IR-DRIFT) spectroscopy and magic
1
room temp.), followed by regioselective 6-O-monosilylation angle spinning (MAS) H NMR confirmed the attachment
with TDSCl and imidazole, afforded the triol 25 in 57% of the scaffold to the resin. The loading of 0.64 mmol/g was
overall yield.
determined by gravimetry.
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FULL PAPER
H2SO4 (31 mL), ammonium molybdate (21 g) and Ce(SO4)2 (1 g)
in water (500 mL), followed by heating at 110 °C for 5 min. Column
chromatography was performed by the flash procedure using
Merck silica gel 60 (230Ϫ100.58 mesh). Elemental analyses were
performed using a Carlo Erba 1108 elemental analyser. Solvents
were dried by standard procedures.
(3-O-Allyl-β-
D-galactopyranosyl)-(1Ǟ4)-[1,2-O-(1-methoxyethyl-
idene)]-α- -glucopyranose (7): 1  Sodium methoxide in methanol
D
(9.3 mL, 9.3 mmol) was added dropwise under argon to a solution
of 5[24] (21 g, 31 mmol) in dry methanol (120 mL). After 4 h, the
mixture was neutralised with Amberlite IR120, filtered and concen-
trated in vacuo. The crude residue was dissolved in dry methanol
(110 mL) and dibutyltin oxide (8.9 g, 35.7 mmol) was added. The
reaction was stirred at 60 °C for 15 h, and then the solvent was
evaporated under reduced pressure. The solid residue was dissolved
in toluene at 60 °C and then tetrabutylammonium iodide (14.3 g,
38.7 mmol) and allyl bromide (26.2 mL, 310 mmol) were added.
After stirring the mixture at 60 °C for 17 h, the solvent was evapo-
rated under reduced pressure and the residue was purified by flash
chromatography (CHCl3/CH3OH, 9:1, ϩ 1% triethylamine) to yield
7 (11.84 g, 87% from 5) as a brown amorphous solid. [α]2D0 ϭ ϩ3.6
Scheme 5. Synthesis of compound 30. Reagents and conditions: a)
1,3-dichloro-5,5-dimethylhydantoin, CH2Cl2; b) 22, imidazole,
CH2Cl2
1
(c ϭ 1, MeOH). H NMR (300 MHz, CD3OD): δ ϭ 1.60 (s, 3 H,
CH3), 3.27 (s, 3 H, OCH3), 3.51Ϫ3.85 (m, 9 H, H-2, H-4, H-5, H-
6a, H-3Ј, H-5Ј, H-6Јa, H-6Јb, CH2ϭCHϪCHH), 4.00 (d, J4Ј,3Ј
ϭ
3.2 Hz, 1 H, H-4Ј), 4.09Ϫ4.30 (m, 4 H, CH2ϭCHϪCHH, H-3, H-
6b, H-2Ј), 4.38 (d, J1Ј,2Ј ϭ 7.8 Hz, 1 H, H-1Ј), 5.12Ϫ5.38 (m, 2 H,
CH2ϭCHϪCH2), 5.69 (d, J1,2 ϭ 5.2 Hz, 1 H, H-1), 5.92Ϫ6.03 (m,
1 H, CH2ϭCHϪCH2) ppm. C18H30O12 (438.92): calcd.C 49.31, H
6.90; found C 49.49, H 6.91.
Conclusion
We have described efficient syntheses of lactosidic scaf-
folds 2 and 3 in solution. Both compounds contain four
orthogonally protected OH groups as diversity sites. Selec-
tive access to these OH groups has been demonstrated in
solution for scaffold 2 through its sequential deprotection
and functionalisation using p-fluorophenyl isocyanate. The
selective deprotection of benzoyl ester and p-methoxybenzyl
and allyl ether units in the presence of a silyl ethereal bond
is particularly noteworthy because it should ensure the ap-
plicability of this strategy to solid phase protocols. As a
proof of concept, alcohol 22, derived from scaffold 2, was
eventually anchored to PS-DES resin through a silyl ethe-
real linkage to obtain a polymer-bound template suitable
for the development of lactose-based libraries of sugar
mimics. The use of compounds 2 and 3 as molecular scaf-
folds for the generation of sugar libraries, both in solution
and in the solid phase, is currently under investigation in
our laboratory.
Complete assignment of the 1H NMR spectrum of 7 was hampered
by extensive overlapping of signals. Therefore, an analytical sample
of 7 (30 mg) was submitted to standard acetylation (Ac2O, py) and
the resulting pentaacetylated product was fully characterised by
NMR spectroscopy. 1H NMR (300 MHz, CDCl3): δ ϭ 1.68 (s, 3
H, CH3), 1.94Ϫ2.16 (m, 15 H, OAc), 3.26 (s, 3 H, OCH3), 3.47
(dd, J3Ј,4Ј ϭ 3.7 Hz, 1 H, H-3Ј), 3.59 (d, J4,5 ϭ 9.4 Hz, 1 H, H-4),
3.82Ϫ3.93 (m, 3 H, H-5Ј, H-5, CH2ϭCHϪCHH), 4.05Ϫ4.12 (m,
4 H, H-6a, 2 H-6Ј, CH2ϭCHϪCHH), 4.22 (br. dd, J6a,6b
ϭ
11.8 Hz, 1 H, H-6b), 4.29 (m, 1 H, H-2), 4.50 (d, J1Ј,2Ј ϭ 8.0 Hz, 1
H, H-1Ј), 5.05 (t, J2Ј,3Ј ϭ 10.0 Hz, 1 H, H-2Ј), 5.12Ϫ5.23 (m, 2 H,
CH2ϭCHϪCH2), 5.39 (d, 1 H, H-4Ј), 5.51 (br. s, 1 H, H-3), 5.62
(d, J1,2 ϭ 5.2 Hz, 1 H, H-1), 5.68Ϫ5.81 (m, 1 H, CH2ϭCHϪCH2)
ppm. 13C NMR (75.43 MHz, CDCl3): δ ϭ 14.3 (CH3), 21.0, 21.2,
21.3, 21.7, 22.0 (5 OAc), 57.7 (OCH3), 59.7 (CH2ϭCHϪCH2),
62.2, 62.9 (C-6, C-6Ј), 67.2, 71.6, 71.9, 75.4, 76.9, 76.3, 81.1, 82.3
(C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 91.2 (C-1Ј), 106.0 (C-
1), 117.2 [C(OMe)Me], 117.7 (CH2ϭCHϪCH2), 136.8 (CH2ϭ
CHϪCH2), 172.2, 172.7, 180.4 (CϭO) ppm.
Benzyl [3-O-Allyl-4,6-O-benzylidene-2-O-(tert-butyldimethylsilyl)-
Experimental Section
β-D-galactopyranosyl]-(1Ǟ4)-2-O-acetyl-3,6-di-O-(tert-butyldi-
methylsilyl)]-α,β-D-glucopyranoside (10α and 10β): Benzyl alcohol
(12.6 mL, 122 mmol) was added under argon to a solution of 7
1
General Remarks: H NMR and 13C NMR spectra were recorded
˚
with Varian Gemini 200, Bruker AC 300 and Bruker Avance 400
spectrometers at 298 K. When required for unambiguous charac-
terization, COSY, TOCSY and HMQC spectra were also recorded.
In the description of the 13C NMR spectra, signals corresponding
to aromatic carbon atoms are omitted. Solid phase NMR spectra
were acquired with a Varian Unity 400 MHz equipped with an HR-
MAS Nanoprobe. Optical rotations were measured at room tem-
(5.36 g, 12.2 mmol) in dry CH3CN (30 mL); 3-A molecular sieves
were added and the mixture was stirred at 0 °C for 30 min. Trifluor-
omethanesulfonic acid (4.9 mL of a 0.5  solution in dry CH3CN),
which was cooled to 0 °C for 5 min, was quickly added. After
10 min, the mixture was neutralized with Et3N, filtered through a
pad of Celite, and then the filtrate was evaporated. The crude prod-
uct was purified by flash column chromatography (CHCl3/CH3OH,
perature using a PerkinϪElmer 241 polarimeter. TLC was per- 95:5 ϩ 1% triethylamine) to yield 8 (4.40 g, 70%, α/β mixture) as
formed on Merck silica gel 60 F254 plates (0.25-mm thickness), and
spots were visualized by spraying with a solution comprising
an amorphous white solid. The anomeric mixture of 8 was not
characterised further; rather, it was submitted directly to the next
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S. Castoldi, M. Cravini, F. Micheli, E. Piga, G. Russo, P. Seneci, L. Lay
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step. A catalytic amount of camphorsulfonic acid was added to a
0.86Ϫ0.92 (3 s, 27 H, CH3 tBu), 3.24 (br. d, J5,4 ϭ 9.5 Hz, 1 H, H-
solution of 8 and benzaldehyde dimethyl acetal (2.6 g, 17.1 mmol) 5), 3.30 (dd, J3Ј,4Ј ϭ 3.6, J3Ј,2Ј ϭ 9.3 Hz, 1 H, H-3Ј), 3.34 (br. s, 1
in dry CH3CN (30 mL). After 30 min, the solution was neutralised
with Et3N and concentrated in vacuo to obtain crude 9. tert-Butyl-
H, H-5Ј), 3.44 (t, J3,4 ϭ 8.8 Hz, 1 H, H-3), 3.52 (t, J2,3 ϭ 7.5 Hz,
1 H, H-2), 3.81 (t, 1 H, H-2Ј), 3.88 (br. d, J6a,6b ϭ 10.5 Hz, 1 H,
dimethylsilyl trifluoromethanesulfonate (6.1 mL, 16.6 mmol) was H-6a), 4.06 (d, 1 H, H-6Јa), 4.08Ϫ4.18 (m, 4 H, CH2ϭCHϪCH2,
added dropwise under argon to a cooled (Ϫ20 °C) solution of 9
and collidine (5.8 mL, 44 mmol) in dry DMF (25 mL). The mixture
was stirred at room temperature overnight. The reaction mixture
was washed with H2O and then the organic layer was dried
(Na2SO4), filtered and concentrated in vacuo. The residue was puri-
H-4, H-6b), 4.22 (d, 1 H, H-4Ј), 4.35 (d, J1,2 ϭ 7.3 Hz, 1 H, H-1),
4.44 (d, J6Јa,6Јb ϭ 12.2 Hz, 1 H, H-6Јb), 4.53 (d, 1 H, CHHPh),
4.61 (d, 1 H, CHHPh), 4.63 (d, J1Ј,2Ј ϭ 7.3 Hz, 1 H, H-1Ј), 4.88 (d,
Jgem ϭ 11.3 Hz, 1 H, CHHPh), 5.18Ϫ5.30 (m, 3 H, CH2ϭ
CHϪCH2, CHHPh), 5.51 (s, 1 H, CHPh), 5.92Ϫ6.01 (m, 1 H,
fied by flash chromatography (petroleum ether/EtOAc, 95:5). First CH2ϭCHϪCH2), 7.10Ϫ7.55 (m, 15 H, HAr) ppm. 13C NMR
elution gave compound 10α (1.34 g, 16%) as a clear oil. [α]2D0
ϭ
(100.58 MHz, CDCl3): δ ϭ Ϫ4.4, Ϫ4.3, Ϫ4.29, Ϫ4.20, Ϫ3.7
Ϫ10.4 (c ϭ 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ (CH3Si), 18.20, 18.25 (Cq tBu), 26.0, 26.1 (CH3 tBu), 61.4 (CH2ϭ
0.00Ϫ0.10 (6 s, 18 H, CH3Si), 0.82Ϫ0.93 (3 s, 27 H, CH3 tBu), 2.05 CHϪCH2), 70.6, 70.8, 69.1, 75.6 (2 CH2Ph, C-6, C-6Ј), 67.0, 71.4,
(s, 3 H, OAc), 3.19Ϫ3.23 (m, 2 H, H-5, H-5Ј), 3.43Ϫ3.50 (m, 2 H, 73.5, 74.9, 75.0, 75.4, 77.6, 83.5 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј,
H-6aЈ, H-3Ј), 3.80 (m, 2 H, H-4, H-2Ј), 3.91Ϫ4.10 (m, 5 H, H-6Јb,
C-4Ј, C-5Ј), 101.3, 102.2, 102.6, (C-1, C-1Ј, CHPh), 117.1 (CH2ϭ
H-6a, H-3, CH2ϭCHϪCH2), 4.14 (d, J4Ј,3Ј ϭ 3.6 Hz, 1 H, H-4Ј), CHϪCH2), 135.3 (CH2ϭCHϪCH2) ppm. C54H84O11Si3 (993.49):
4.25 (d, J6aЈ,6bЈ ϭ 12.0 Hz, 1 H, H-6b), 4.49 (d, J1Ј,2Ј ϭ 7.9 Hz 1 H,
H-1Ј), 4.53Ϫ4.64 (m, 2 H, CHHPh, H-2), 5.02 (d, J1,2 ϭ 3.8 Hz, 1
H, H-1), 5.10Ϫ5.30 (m, 2 H, CH2ϭCHϪCH2), 5.44 (s, 1 H,
CHPh), 5.85Ϫ5.98 (m, 1 H, CH2ϭCHϪCH2), 7.35Ϫ7.51 (m, 10
H, HAr) ppm. 13C NMR (100.58 MHz, CDCl3): δ ϭ Ϫ4.3, Ϫ4.0,
2.1 (CH3Si), 19.4 (Cq tBu), 26.3 (CH3 tBu), 61.5 (CH2ϭ
CHϪCH2), 69.1, 69.2, 71.8 (CH2Ph, C-6, C-6Ј), 61.5, 61.5, 74.9,
75.7, 76.2, 76.9, 81.0, 81.8 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-
5Ј), 101.8, 102.1, 102.9 (C-1, C-1Ј, CHPh), 117.5 (CH2ϭ
CHϪCH2), 135.7 (CH2ϭCHϪCH2), 169.5 (CϭO) ppm.
C49H80O12Si3 (945.41): calcd. C 62.25, H 8.53; found C 62.48, H
8.51. Further elution gave compound 10β (3.35 g, 42%) as a clear
calcd. C 65.28, H 8.52; found C 65.04, H 8.49.
Benzyl (3-O-Allyl-4,6-O-benzylidene-β-D-galactopyranosyl)-(1Ǟ4)-
3-O-benzyl-6-O-(thexyldimethylsilyl)-β-
D-glucopyranoside (15): 1 
Tetrabutylammonium fluoride in dry THF (7.8 mL) was added un-
der argon to a cooled (Ϫ30 °C) solution of 13 (2.35 g, 2.36 mmol)
in dry THF (20 mL). The mixture was stirred at Ϫ30 °C for 1 h,
at 0 °C for 12 h and, finally, overnight at room temperature. The
mixture was washed with H2O and then the organic layer was dried
(Na2SO4), filtered and concentrated in vacuo to yield crude 14,
which was used directly in the next step without purification. Imi-
dazole (265 mg, 3.89 mmol) was added under argon to a cooled (0
°C) solution of 14 (1.2 g, 1.77 mmol) in dry DMF (10 mL) whilst
stirring; thexyldimethylsilyl chloride (0.38 mL, 1.95 mmol) was
then added dropwise. After 4 h, the reaction mixture was diluted
with EtOAc and washed with satd. NaHCO3 and then with H2O;
the organic layer was dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by flash chromatography (petro-
leum ether/EtOAc, 9:1) to yield 15 (0.99 g, 53% from 13) as a clear
1
oil. [α]2D0 ϭ Ϫ17.7 (c ϭ 1, CHCl3). H NMR (400 MHz, CDCl3):
δ ϭ 0.02Ϫ0.20 (6 s, 18 H, CH3Si), 0.89Ϫ0.94 (3 s, 27 H, CH3 tBu),
2.10 (s, 1 H, OAc), 3.18Ϫ3.30 (m, 3 H, H-3Ј, H-5, H-5Ј), 3.64 (t,
J3,2 ϭ J3,4 ϭ 9.0 Hz, 1 H, H-3), 3.84 (t, J2Ј,1Ј ϭ J2Ј,3Ј ϭ 8.3 Hz, 1
H, H-2Ј), 3.86Ϫ3.92 (m, 2 H, H-4, H-6a), 3.98 (br. dd, J6Јa,6Јb
ϭ
11.3 Hz, 1 H, H-6Јa), 4.06Ϫ4.18 (m, 3 H, H-6b, CH2ϭCHϪCH2),
4.19 (d, J4Ј,3Ј ϭ 3.6 Hz, 1 H, H-4Ј), 4.30 (br. dd, 1 H, H-6Јb), 4.42
oil. [α]2D0 ϭ ϩ11.6 (c ϭ 1, CHCl3). H NMR (300 MHz, CDCl3):
1
(d, J1,2 ϭ 8.0 Hz, 1 H, H-1), 4.58 (d, 1 H, H-1Ј), 4.62 (d, Jgem
ϭ
δ ϭ 0.11Ϫ0.19 (2 s, 6 H, CH3Si), 0.83Ϫ0.98 (4 s, 12 H, CH3 thexyl),
1.65 (m, 1 H, CH thexyl), 3.13 (s, 1 H, H-5Ј), 3.30Ϫ3.40 (m, 2 H,
H-3, H-5), 3.37 (dd, J3Ј,4Ј ϭ 3.5, J3Ј,2Ј ϭ 9.8 Hz, 1 H, H-3Ј), 3.55
(t, J2,3 ϭ 7.2 Hz, 1 H, H-2), 3.60 (d, J6b,6a ϭ 9.0 Hz, 1 H, H-6b),
3.92 (br, 2 H, H-6a, H-6Јa), 3.98 (t, J2Ј,3Ј ϭ 8.3 Hz, 1 H, H-2Ј),
4.10 (d, 1 H, H-4Ј), 4.13Ϫ4.16 (m, 3 H, H-6Јb, CH2ϭCHϪCH2),
4.20 (t, J4,3 ϭ J4,5 ϭ 6.0 Hz, 1 H, H-4), 4.37 (d, J1,2 ϭ 7.3 Hz, 1
H, H-1), 4.59 (d, 1 H, CHHPh), 4.68 (d, J1Ј,2Ј ϭ 7.7 Hz, 1 H, H-
1Ј), 4.85 (d, 1 H, CHHPh), 4.87 (d, Jgem ϭ 11.5 Hz, 1 H, CHHPh),
5.08 (d, Jgem ϭ 11.3 Hz, 1 H, CHHPh), 5.25 (br. dd, 2 H, CH2ϭ
CHϪCH2), 5.49 (s, 1 H, CHPh), 5.90Ϫ6.00 (m, 1 H, CH2ϭ
12.5 Hz, 1 H, CHHPh), 4.86 (d, 1 H, CHHPh), 4.94 (t, 1 H, H-2),
5.16Ϫ5.32 (m, 2 H, CH2ϭCHϪCH2), 5.48 (s, 1 H, CHPh),
5.90Ϫ6.01 (m, 1 H, CH2ϭCHϪCH2), 7.25Ϫ7.51 (m, 10 H, HAr
)
ppm. 13C NMR (100.58 MHz, CDCl3): δ ϭ Ϫ4.4, Ϫ4.1, Ϫ3.9,
Ϫ3.0, Ϫ2.4 (CH3Si), 18.2, 18.6, 18.8 (Cq tBu), 21.6 (CH3Ac), 26.1,
26.3, 26.4 (CH3 tBu), 61.5 (CH2ϭCHϪCH2), 69.4, 69.8, 71.0
(CH2Ph, C-6, C-6Ј), 67.1, 71.0, 73.7, 74.1, 74.5, 74.7, 77.1, 81.0 (C-
2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 100.2 (C-1), 101.7, 102.3
(C-1Ј, CHPh), 117.5 (CH2ϭCHϪCH2), 135.7 (CH2ϭCHϪCH2),
169.8 (CϭO) ppm. C49H80O12Si3 (945.41): calcd. C 62.25, H 8.53;
found C 62.04, H 8.54.
CHϪCH2), 7.20Ϫ7.51 (m, 15 H, HAr
)
ppm. 13C NMR
Benzyl [3-O-Allyl-4,6-O-benzylidene-2-O-(tert-butyldimethylsilyl)-
(75.43 MHz, CDCl3): δ ϭ Ϫ3.4, Ϫ2.9 (CH3Si), 18.6, 18.7, 20.3,
20.4 (CH3 thexyl), 29.7 (Cq thexyl), 34.1 (CH thexyl), 61.6 (CH2ϭ
CHϪCH2), 69.2, 70.6, 70.9, 75.1 (2 CH2Ph, C-6, C-6Ј), 63.3, 66.8,
70.9, 73.8, 74.2, 75.6, 76.5, 79.0 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј,
C-4Ј, C-5Ј), 101.2, 101.4, 103.3 (C-1, C-1Ј, CHPh), 117.5 (CH2ϭ
CHϪCH2), 134.9 (CH2ϭCHϪCH2) ppm. C44H60O11Si (792.39):
calcd. C 66.64, H 7.63; found C 66.49, H 7.65.
β-
D
-galactopyranosyl]-(1Ǟ4)-3-O-benzyl-2,6-di-O-(tert-butyldi-
-glucopyranoside (13): 0.15  NaOH in ethanol
methylsilyl)-β-
D
(10.6 mL) was added to a solution of 10β (750 mg, 0.78 mmol) in
EtOH (4 mL). The reaction mixture was stirred overnight at 40 °C
and then concentrated in vacuo; the residue was dissolved in dry
DMF (5 mL) under argon. Benzyl bromide (0.14 mL, 1.18 mmol)
and NaH (56 mg, 2.37 mmol) were added sequentially. When TLC
analysis indicated completion of the reaction (5 h), the mixture was
quenched with methanol, diluted with CH2Cl2 and washed with
Benzyl (3-O-Allyl-4,6-O-benzylidene-β-
D-galactopyranosyl)-(1Ǟ4)-
2-O-benzoyl-3-O-benzyl-6-O-(thexyldimethylsilyl)-β-
D
-gluco-
H2O; the organic layer was dried (Na2SO4), filtered and concen- pyranoside (16): Et3N (2.7 mL, 19.4 mmol) was added under argon
trated in vacuo. The residue was purified by flash chromatography
(petroleum ether/EtOAc, 9:1) to yield 13 (630 mg, 81% from 10β)
as an amorphous white solid. [α]2D0 ϭ Ϫ15.6 (c ϭ 1, CHCl3). 1H
to a cooled (Ϫ40 °C) solution of 15 (860 mg, 1.08 mmol) in dry
CH3CN (10 mL). Whilst stirring, benzoyl cyanide (3.24 mL of a
0.5  solution in dry CH3CN) was added dropwise. After 24 h,
NMR (400 MHz, CDCl3): δ ϭ Ϫ0.01Ϫ0.12 (6 s, 18 H, CH3Si), the reaction was diluted with CH2Cl2 and washed with saturated
2858  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 2853Ϫ2862

Solution Synthesis of Two Orthogonally Protected Lactosides
FULL PAPER
aqueous NaHCO3; the organic layer was dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (petroleum ether/EtOAc, 7:3) to yield 16 (407 mg, 50%) as a
white oil. [α]2D0 ϭ ϩ12.3 (c ϭ 1, CHCl3). 1H NMR (300 MHz,
dry CH2Cl2 (1 mL). TLC analysis indicated complete disappear-
ance of starting material after 5 h. The reaction mixture was
quenched with methanol, diluted with CH2Cl2 and washed with
H2O; the organic layer was dried (Na2SO4), filtered and concen-
CDCl3): δ ϭ 0.13Ϫ0.19 (2 s, 6 H, CH3Si), 0.83Ϫ0.90 (4 s, 12 H, trated in vacuo. The residue was purified by flash chromatography
CH3 thexyl), 1.65 (m, 1 H, CH thexyl), 3.12 (br. s, 1 H, H-5Ј),
(petroleum ether/EtOAc, 8:2) to yield 17 (31 mg, 60% from 2) as a
3.13Ϫ3.39 (m, 2 H, H-5, H-3Ј), 3.78 (t, J3,2 ϭ J3,4 ϭ 9.2 Hz, 1 H, white amorphous solid. [α]2D0 ϭ Ϫ11.4 (c ϭ 1, CHCl3). H NMR
H-3), 3.86Ϫ3.98 (m, 3 H, H-6b, H-2Ј, H-6Јa), 4.09Ϫ4.24 (m, 6 H, (300 MHz, CDCl3): δ ϭ 0.06Ϫ0.10 (2 s, 6 H, CH3Si), 0.79Ϫ0.89
1
CH2ϭCHϪCH2, H-4, H-6a, H-4Ј, H-6Јb), 4.51 (d, J1,2 ϭ 8.1 Hz,
(4 s, 12 H, CH3 thexyl), 1.59 (m, 1 H, CH thexyl), 3.18Ϫ3.28 (m,
1 H, H-1), 4.58 (d, 1 H, CHHPh), 4.68 (d, 1 H, CHHPh), 4.70 (d, 3 H, H-3Ј, H-5Ј, H-5), 3.39 (br. dd, J6Јa,6Јb ϭ 11.4 Hz, 1 H, H-6Јa),
J1Ј,2Ј ϭ 7.1 Hz, 1 H, H-1Ј), 4.81 (d, Jgem ϭ 12.6 Hz, 1 H, CHHPh), 3.71Ϫ3.79 (m, 2 H, H-3, H-6Јb), 3.96Ϫ4.18 (m, 4 H, H-4, H-6a,
4.97 (d, Jgem ϭ 11.5 Hz, 1 H, CHHPh), 5.28Ϫ5.36 (m, 3 H, CH2ϭ CH2ϭCHϪCH2), 4.25 (d, J4Ј,3Ј ϭ 3.0 Hz, 1 H, H-4Ј), 4.34 (d,
CHϪCH2, H-2), 5.48 (s, 1 H, CHPh), 5.88Ϫ6.02 (m, 1 H, CH2ϭ
CHϪCH2), 7.00Ϫ7.97 (m, 20 H, HAr
ppm. 13C NMR
(75.43 MHz, CDCl3): δ ϭ Ϫ3.3, Ϫ2.8 (CH3Si), 18.7, 18.8, 20.3, 12.4 Hz, 1 H, CHHPh), 5.02 (d, Jgem ϭ 11.6 Hz, 1 H, CHHPh),
20.4 (CH3 thexyl), 29.7 (Cq thexyl), 34.1 (CH thexyl), 61.4 (CH2ϭ 5.21 (t, J2,1 ϭ J2,3 ϭ 9.5 Hz, 1 H, H-2), 5.25Ϫ5.38 (m, 3 H, H-2Ј,
J6a,6b ϭ 12.5 Hz, 1 H, H-6b), 4.55 (d, 1 H, H-1), 4.58 (d, 1 H,
)
CHHPh), 4.56Ϫ4.68 (m, 2 H, CHHPh, H-1Ј), 4.80 (d, Jgem
ϭ
CHϪCH2), 69.1, 69.6, 73.7 (C-6, C-6Ј, CH2Ph), 66.7, 70.9, 73.1, CH2ϭCHϪCH2), 5.51 (s, 1 H, CHPh), 5.85Ϫ5.95 (m, 1 H, CH2ϭ
73.7, 75.6, 79.0, 81.4 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), CHϪCH2), 6.90Ϫ7.90 (m, 24 H, HAr), 10.82 (s, 1 H, NH) ppm.
99.4, 101.1, 103.3 (C-1, C-1Ј, CHPh), 117.6 (CH2ϭCHϪCH2), 13C NMR (75.46 MHz, CDCl3): δ ϭ Ϫ3.4, Ϫ2.8 (CH3Si), 18.5,
134.8 (CH2ϭCHϪCH2), 165.2 (C ϭ O) ppm. C43H46O12 (754.82): 18.8, 20.2, 20.4 (CH3 thexyl), 29.6 (Cq thexyl), 34.2 (CH thexyl),
calcd. C 68.42, H 6.14; found C 68.54, H 6.12.
61.0 (CH2ϭCHϪCH2), 68.8, 69.6, 70.1, 72.6 (C-6, C-6Ј, 2 CH2Ph),
66.7, 72.6, 75.1, 73.9, 75.3, 75.4, 77.4, 79.8, (C-2, C-3, C-4, C-5, C-
2Ј, C-3Ј, C-4Ј, C-5Ј), 99.1, 101.2 (C-1, C-1Ј, CHPh), 117.8 (CH2ϭ
CHϪCH2), 132.6 (CH2ϭCHϪCH2), 161.2, 165.2 (CϭO, NϪCϭ
O) ppm. C58H68FNO13Si (1033.44): calcd. C 67.36, H 6.63, N 1.35;
found C 67.13, H 6.62, N 1.35.
Benzyl [3-O-Allyl-4,6-O-benzylidene-2-O-(p-methoxybenzyl)-β-D-
galactopyranosyl]-(1Ǟ4)-2-O-benzoyl-3-O-benzyl-6-O-(thexyldi-
methylsilyl)-β- -glucopyranoside (2): p-Methoxybenzyl chloride (58
D
µL, 0.43 mmol), NaH (10 mg, 0.43 mmol) and KI (71 mg,
0.43 mmol) were added under argon to a cooled (Ϫ30 °C) solution
of 16 (192 mg, 0.21 mmol) in dry DMF (2.5 mL). TLC analysis
indicated completion of the reaction after 5 h. The reaction mixture
was quenched with methanol, diluted with CH2Cl2 and washed
with H2O; the organic layer was dried (Na2SO4), filtered and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (toluene/EtOAc, 95:5) to yield 2 (111 mg, 51%) as a yellow oil.
Benzyl [4,6-O-Benzylidene-3-O-(p-fluorophenylcarbamoyl)-2-O-(p-
methoxybenzyl)-β-
benzyl-6-O-(thexyldimethylsilyl)-β-
D
-galactopyranosyl]-(1Ǟ4)-2-O-benzoyl-3-O-
-glucopyranoside (19): Pal-
D
ladium() chloride (36 mg, 0.2 mmol) and NaOAc (62 mg,
0.46 mmol) were added to a solution of 2 (186 mg, 0.18 mmol) in
aqueous acetic acid (3 mL, solution 0.5 ). After 24 h, TLC analy-
sis indicated the complete disappearance of starting material. The
reaction mixture was diluted with CH2Cl2, filtered through a Celite
pad and washed with satd. NaHCO3 until it became neutral; the
organic layer was dried (Na2SO4), filtered and concentrated in va-
cuo to yield crude 18. p-Fluorophenyl isocyanate (53 µL,
0.39 mmol) was added to a solution of 18 in dry CH2Cl2 (3.5 mL).
After 5 h, the reaction mixture was quenched with methanol, di-
luted with CH2Cl2 and washed with H2O; the organic layer was
dried (Na2SO4), filtered and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 8:2)
to yield 19 (104 mg, 52% from 2) as a white amorphous solid. [α]
[α]2D0 ϭ Ϫ10.4 (c ϭ 1, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
1
0.08Ϫ0.11 (2 s, 6 H, CH3Si), 0.82Ϫ0.91 (4 s, 12 H, CH3 thexyl),
1.63 (m, 1 H, CH thexyl), 3.21 (d, 1 H, H-5), 3.29 (br. s, 1 H, H-
5Ј), 3.45 (dd, J3Ј,4Ј ϭ 3.4, J3Ј,2Ј ϭ 9.7 Hz, 1 H, H-3Ј), 3.69Ϫ3.80
(m, 5 H, H-3, H-2Ј, OCH3), 3.97 (br. dd, 1 H, H-6Јa), 4.16 (t, J4,3 ϭ
J4,5 ϭ 9.2 Hz, 1 H, H-4), 4.06Ϫ4.22 (m, 5 H, 2 H-6, H-4Ј, CH2ϭ
CHϪCH2), 4.31 (br. dd, J6Јa,6Јb ϭ 12.3 Hz, 1 H, H-6Јb), 4.52 (d,
J1,2 ϭ 8.1 Hz, 1 H, H-1), 4.58 (d, 1 H, CHHPh), 4.65Ϫ4.77 (m, 4
H, CH2C6H4Ϫp-OMe, CHHPh, H-1Ј), 4.80 (d, Jgem ϭ 12.5 Hz, 1
H, CHHPh), 5.05 (d, Jgem ϭ 11.7 Hz, 1 H, CHHPh), 5.15Ϫ5.22
(m, 3 H, H-2, CH2ϭCHϪCH2), 5.50 (s, 1 H, CHPh), 5.87Ϫ6.00
(m, 1 H, CH2ϭCHϪCH2), 6.81Ϫ7.97 (m, 24 H, HAr) ppm. 13C
NMR (75.43 MHz, CDCl3): δ ϭ Ϫ3.3, 2.9 (CH3Si), 18.7, 18.8,
20.3, 20.5 (CH3 thexyl), 29.7 (Cq thexyl), 34.3 (CH thexyl), 55.3
(OCH3), 60.9 (CH2ϭCHϪCH2), 69.1, 69.5, 71.3 (2 CH2Ph,
CH2C6H4Ϫp-OMe), 74.6, 74.8 (C-6, C-6Ј), 66.5, 73.3, 74.1, 76.1,
76.7, 78.8, 79.6, 80.4 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј),
99.4, 101.4, 102.7 (C-1, C-1Ј, CHPh), 117.1 (CH2ϭCHϪCH2),
132.8 (CH2ϭCHϪCH2), 165.2 (CϭO) ppm. C59H73O13Si
(1018.29): calcd. C 69.59, H 7.23; found C 69.54, H 7.21.
ϭ Ϫ12.2 (c ϭ 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
20
D
0.09Ϫ0.12 (2 s, 6 H, CH3Si), 0.84Ϫ0.90 (4 s, 12 H, CH3 thexyl),
1.64 (m, 1 H, CH thexyl), 3.26 (m, 1 H, H-5), 3.41 (br. s, 1 H, H-
5Ј), 3.72 (s, 3 H, OCH3), 3.73Ϫ3.88 (m, 3 H, H-3, H-6a, H-2Ј),
3.97 (br. dd, 1 H, H-6Јa), 4.06 (dd, J6a,6b ϭ 11.6, J5,6 ϭ 2.6 Hz, 1
H, H-6b), 4.19 (t, J4,3 ϭ J4,5 ϭ 9.1 Hz, 1 H, H-4), 4.31 (br. dd,
J6Јa,6Јb ϭ 12.6 Hz, 1 H, H-6Јb), 4.37 (d, J4Ј,3Ј ϭ 3.5 Hz, 1 H, H-4Ј),
4.53 (d, J1,2 ϭ 8.3 Hz, 1 H, H-1), 4.55Ϫ4.67 (m, 2 H, 2 CHHPh),
4.69Ϫ4.89 (m, 5 H, H-3Ј, H-1Ј, 2 CHHPh, CHHC6H4-p-OMe),
Benzyl
[3-O-Allyl-4,6-O-benzylidene-2-O-(p-fluorophenylcarba- 5.27 (t, J2,3 ϭ 8.2 Hz, 1 H, H-2), 5.07 (d, Jgem ϭ 11.5 Hz, 1 H,
moyl)-β-
(thexyldimethylsilyl)-β-
D
-galactopyranosyl]-(1Ǟ4)-2-O-benzoyl-3-O-benzyl-6-O-
-glucopyranoside (17): 2,3-Dichloro-5,6-di-
cyano-1,4-benzoquinone (13 mg, 0.06 mmol) was added to a solu-
CHHC6H4Ϫp-OMe), 5.49 (s, 1 H, CHPh), 6.75Ϫ8.00 (m, 28 H,
HAr), 10.61 (s, 1 H, NH) ppm. 13C NMR (75.43 MHz, CDCl3):
δ ϭ Ϫ3.3, 2.9 (CH3Si), 18.6, 18.7, 20.3, 20.4 (CH3 thexyl), 27.4
D
tion of 2 (50 mg, 0.05 mmol) in CH2Cl2 (0.95 mL) and H2O (0.10 (Cq thexyl), 34.2 (CH thexyl), 55.2 (OCH3), 60.9, 68.8, 69.5, 74.5,
mL). The mixture was stirred for 3 h at room temperature before 74.7 (C6, C-6Ј, 2 CH2Ph, CH2C6H4Ϫp-OMe), 66.1, 73.3, 74.2,
it was diluted with CH2Cl2 and washed with satd. NaHCO3; the
organic layer was dried (Na2SO4), filtered and concentrated in va-
cuo to yield crude 16. p-Fluorophenyl isocyanate (18 µL,
76.2, 76.5, 80.5 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 99.2,
101.1, 102.7 (C-1, C-1Ј, CHPh), 160.5, 162.5 (CϭO, NϪCϭO)
ppm. C63H72FNO14Si (1113.47): calcd. C 67.90, H 6.51, N 1.26;
0.17 mmol) was added to a solution of 16 (45 mg, 0.05 mmol) in found C 68.04, H 6.52, N 1.26.
Eur. J. Org. Chem. 2004, 2853Ϫ2862
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2859

S. Castoldi, M. Cravini, F. Micheli, E. Piga, G. Russo, P. Seneci, L. Lay
FULL PAPER
Benzyl (3-O-Allyl-4,6-O-benzylidene-2-O-(p-methoxybenzyl)-β-
D
-
ppm. C51H54O13 (874.97): calcd. C 70.01, H 6.22; found C 70.19,
H 6.23.
galactopyranosyl)-(1Ǟ4)-3-O-benzyl-2-O-(p-fluorophenyl-
carbamoyl)-6-O-(thexyldimethylsilyl)-β- -glucopyranoside (21): 0.15
D
Benzyl (3-O-Allyl-4,6-O-benzylidene-β-
D-galactopyranosyl)-(1Ǟ4)-
 Sodium hydroxide in EtOH (1.64 mL) was added to a solution
of 2 (146 mg, 0.12 mmol) in EtOH (1.5 mL) and then stirred for
36 h. The reaction mixture was diluted with CH2Cl2 and washed
with H2O until it became neutral; the organic layer was dried
(Na2SO4), filtered and concentrated in vacuo to yield 20. p-Fluoro-
phenyl isocyanate (51 µL, 0.37 mmol) was added to a solution of
20 in dry CH2Cl2 (3 mL). After 6 h, the reaction mixture was
quenched with methanol, diluted with CH2Cl2 and washed with
H2O; the organic layer was dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by flash chromatography
(toluene/EtOAc, 95:5) to yield 21 (117 mg, 90% from 2) as a yellow
6-O-(thexyldimethylsilyl)-α- -glucopyranoside (25): 0.15  NaOH
D
in ethanol (5.9 mL) was added to a solution of 10α (0.42 g, 0.44
mmol) in EtOH (2 mL); the mixture was stirred overnight at 40 °C
then concentrated in vacuo. Crude alcohol 23 was dissolved under
argon in dry THF (4.0 mL) and then cooled to Ϫ30 °C. 1  Tetra-
butylammonium fluoride (1.45 mL) was added under argon; the
mixture was stirred at Ϫ30 °C for 1 h and then overnight at room
temperature. The mixture was washed with H2O, and the organic
layer was dried (Na2SO4), filtered and concentrated in vacuo to
yield crude 24, which was used directly in next step without purifi-
cation. Imidazole (54 mg, 0.79 mmol) was added under argon to a
cooled (0 °C) solution of 24 in dry DMF (5 mL) whilst stirring;
thexyldimethylsilyl chloride (0.08 mL, 0.40 mmol) was added drop-
wise. After 4 h, the reaction mixture was diluted with EtOAc and
washed with satd. NaHCO3 and then with H2O; the organic layer
was dried (Na2SO4), filtered and concentrated in vacuo. The resi-
due was purified by flash chromatography (petroleum ether/EtOAc,
9:1) to yield 25 (176 mg, 57% from 10α) as a clear oil. [α]2D0 ϭ Ϫ10.7
(c ϭ 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 0.07Ϫ0.13 (2 s,
6 H, CH3Si), 0.89Ϫ0.91 (4 s, 12 H, CH3 thexyl), 1.62 (m, 1 H, CH
thexyl), 3.39 (dd, J3Ј,4Ј ϭ 3.7, J3Ј,2Ј ϭ 9.6 Hz, 1 H, H-3Ј), 3.44 (s, 1
H, H-5Ј), 3.51Ϫ3.58 (m, 2 H, H-2, H-5), 3.71Ϫ3.95 (m, 5 H, H-3,
H-4, H-6a, H-6b, H-2Ј), 4.04 (d, J6Јa,6Јb ϭ 12.6, J6Ј,5Ј ϭ 1.3 Hz, 1
H, H-6Јa), 4.15Ϫ4.23 (m, 3 H, H-4Ј, CH2ϭCHϪCH2), 4.29 (d, 1
H, H-6Јb), 4.41 (d, J1Ј,2Ј ϭ 7.8 Hz, 1 H, H-1Ј), 4.52 (d, 1 H,
1
oil. [α]2D0 ϭ Ϫ11.4 (c ϭ 1, CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 0.13Ϫ0.19 (2 s, 6 H, CH3Si), 0.78Ϫ0.89 (4 s, 12 H, CH3 thexyl),
1.60 (m, 1 H, CH thexyl), 3.05 (br. d, J5,4 ϭ 9.6 Hz, 1 H, H-5),
3.28 (br. s, 1 H, H-5Ј), 3.34 (t, J3,2 ϭ J3,4 ϭ 9.3 Hz, 1 H, H-3), 3.44
(dd, J3Ј,4Ј ϭ 3.6, J3Ј,2Ј ϭ 9.7 Hz, 1 H, H-3Ј), 3.68Ϫ3.73 (m, 2 H,
H-2Ј, H-6a), 3.75 (s, 3 H, OCH3), 3.96 (br. d, 1 H, H-6Јa), 4.04 (br.
d, 1 H, H-6b), 4.08 (t, 1 H, H-4), 4.16Ϫ4.23 (m, 4 H, H-1, H-4Ј,
CH2ϭCHϪCH2), 4.27 (d, J6Јa,6Јb ϭ 12.1 Hz, 1 H, H-6Јb), 4.49 (d,
Jgem ϭ 11.7 Hz, 1 H, CHHC6H4-p-OMe), 4.52 (d, 1 H, CHHPh),
4.61 (d, 1 H, CHHPh), 4.67 (d, J1Ј,2Ј ϭ 7.1 Hz, 1 H, H-1Ј), 4.69 (d,
Jgem ϭ 10.5 Hz, 1 H, CHHPh), 4.80 (d, Jgem ϭ 12.3 Hz, 1 H,
CHHPh), 4.90 (t, J2,1 ϭ 9.1 Hz, 1 H, H-2), 5.15Ϫ5.32 (m, 3 H,
CH2ϭCHϪCH2, CHHC6H4Ϫp-OMe), 5.50 (s,
1 H, CHPh),
5.86Ϫ6.00 (m, 1 H, CH2ϭCHϪCH2), 6.72Ϫ7.40 (m, 23 H, HAr),
10.84 (s, 1 H, NH) ppm. 13C NMR (75.43 MHz, CDCl3): δ ϭ Ϫ3.4,
Ϫ3.0 (CH3Si), 18.5, 18.7, 20.2, 20.4 (CH3 thexyl), 29.6 (Cq thexyl),
34.1 (CH thexyl), 52.4 (OCH3), 60.4 (CH2ϭCHϪCH2), 68.8, 70.0,
71.4, 75.0, 75.1 (2 CH2Ph, CH2C6H4Ϫp-OMe, C-6, C-6Ј), 67.4,
74.1, 75.7, 76.0, 76.2 78.8, 79.2, 80.8 (C-2, C-3, C-4, C-5, C-2Ј, C-
3Ј, C-4Ј, C-5Ј), 98.1, 101.5, 102.5 (C-1, C-1Ј, CHPh), 117.4 (CH2ϭ
CHϪCH2), 133.9 (CH2ϭCHϪCH2), 160.5 (NϪCϭO) ppm.
C59H72FNO13Si (1050.29): calcd. C 67.47, H 6.91, N 1.33; found
C 67.32, H 6.90, N 1.33.
CHHPh), 4.72 (d, Jgem ϭ 11.9 Hz, 1 H, CHHPh), 4.94 (dd, J1,2
ϭ
3.9 Hz, 1 H, H-1), 5.18Ϫ5.36 (m, 2 H, CH2ϭCHϪCH2), 5.49 (s, 1
H, CHPh), 5.89Ϫ6.01 (m, 1 H, CH2ϭCHϪCH2), 7.22Ϫ7.50 (m,
10 H, HAr) ppm. 13C NMR (75.43 MHz, CDCl3): δ ϭ Ϫ3.3, Ϫ3.2
(CH3Si), 18.6, 18.7, 20.3, 20.4 (CH3 thexyl), 25.2 (Cq thexyl), 34.1
(CH thexyl), 61.9 (CH2ϭCHϪCH2), 69.0, 69.5, 70.6 (C-6, C-6Ј,
CH2Ph), 66.9, 69.8, 70.7, 70.9, 72.5, 72.6, 78.9, 80.8 (C-2, C-3, C-
4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 97.4, 101.1, 103.7 (C-1, C-1Ј,
CHPh), 117.9 (CH2ϭCHϪCH2), 134.6 (CH2ϭCHϪCH2) ppm.
C37H54O11Si (702.90) Calcd. C 63.22, H 7.74; found C 63.25, H
7.89.
Benzyl
[3-O-Allyl-4,6-O-benzylidene-2-O-(p-methoxybenzyl)-β-
D-
galactopyranosyl]-(1Ǟ4)-2-O-benzoyl-3-O-benzyl-β-
D
-gluco-
pyranoside (22): 1  Tetrabutylammonium fluoride in dry THF (47
µL) was added under argon to a cooled (Ϫ30 °C) solution of 2
(40 mg, 0.03 mmol) in dry THF (1 mL). The mixture was stirred 2-O-benzyl-6-O-(thexyldimethylsilyl)-α-
Benzyl (3-O-Allyl-4,6-O-benzylidene-β-
D
-galactopyranosyl)-(1Ǟ4)-
D-glucopyranoside (26): Di-
at Ϫ30 °C for 3 h then at 0 °C for 5 h. The reaction mixture was
diluted with EtOAc and washed with H2O; the organic layer was
butyltin oxide (240 mg, 0.96 mmol) was added to a solution of 25
(580 mg, 0.84 mmol) in dry methanol (5 mL). The reaction mixture
dried (Na2SO4), filtered and concentrated in vacuo. The residue was stirred at 60 °C for 15 h and then the solvent was evaporated
was purified by flash chromatography (toluene/EtOAc, 7:3) to yield
under reduced pressure. The solid residue was dissolved in toluene
(15 mL) at 60 °C and then tetrabutylammonium iodide (380 mg,
1
22 (22 mg, 87%) as a clear oil. [α]2D0 ϭ Ϫ11.1 (c ϭ 1, CHCl3). H
NMR (300 MHz, CDCl3): δ ϭ 3.27 (br. s, 1 H, H-5Ј), 3.45 (br. d, 1.04 mmol) and benzyl bromide (1.0 mL, 8.4 mmol) were added.
1 H, H-5), 3.51 (dd, J3Ј,2Ј ϭ 9.7, J3Ј,4Ј ϭ 3.4 Hz, 1 H, H-3Ј), After stirring the mixture at 60 °C for 17 h, the solvent was evapo-
3.69Ϫ3.88 (m, 7 H, H-3, H-2Ј, H-6a, H-6b, OCH3), 4.00 (d, 1 H, rated under reduced pressure and the residue was purified by flash
H-6Јa), 4.17 (t, J4,3 ϭ J4,5 ϭ 9.2 Hz, 1 H, H-4), 4.18Ϫ4.29 (m, 3 chromatography (CHCl3/CH3OH, 9:1, ϩ 1% triethylamine) to yield
H, CH2ϭCHϪCH2, H-4Ј), 4.31 (d, J6Јa,6Јb ϭ 12.3 Hz, 1 H, H-6Јb), 26 (570 mg, 88%) as an amorphous brown solid. [α]2D0 ϭ ϩ15.5 (c ϭ
4.52 (d, J1,2 ϭ 8.1 Hz, 1 H, H-1), 4.58 (d, 1 H, CHHPh), 4.70Ϫ4.78
(m, 4 H, H-1Ј, CHHC6H4Ϫp-OMe, CH2Ph), 4.80 (d, Jgem
12.6 Hz, H, CHHPh), 5.07 (d, Jgem 11.7 Hz,
CHHC6H4Ϫp-OMe), 5.26 (t, J2,3 ϭ 9.1 Hz, 1 H, H-2), 5.18Ϫ5.40
1, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 0.06Ϫ0.13 (2 s, 6 H,
CH3Si), 0.82Ϫ0.96 (4 s, 12 H, CH3 thexyl), 1.62 (m, 1 H, CH
H, thexyl), 3.33Ϫ3.44 (m, 2 H, H-5, H-5Ј), 3.45Ϫ3.62 (m, 4 H, H-3,
H-4, H-6a, H-6Јa), 3.66 (dd, J3Ј,4Ј ϭ 3.5, J3Ј,2Ј ϭ 9.6 Hz, 1 H, H-
ϭ
1
ϭ
1
(m, 2 H, CH2ϭCHϪCH2), 5.52 (s, 1 H, CHPh), 5.89Ϫ6.10 (m, 1 3Ј), 3.95Ϫ4.20 (m, 5 H, CH2ϭCHϪCH2, H-2, H-6b, H-6Јb), 4.30
H, CH2ϭCHϪCH2), 6.98Ϫ8.05 (m, 24 H, HAr) ppm. 13C NMR (d, 1 H, H-4Ј), 4.36Ϫ4.45 (m, 2 H, H-1, CHHPh), 4.58 (br. d, 2 H,
(75.43 MHz, CDCl3): δ ϭ 55.3 (OCH3), 61.0 (CH2ϭCHϪCH2), 2 CHHPh), 4.71Ϫ4.85 (m, 2 H, H-1Ј, CHHPh), 5.05Ϫ5.22 (m, 2
69.1, 70.5, 71.3, 74.6, 75.1 (2 CH2Ph, CH2C6H4Ϫp-OMe, C-6, C-
H, CH2ϭCHϪCH2) 5.54 (s, 1 H, CHPh), 5.61 (t, J1Ј,2Ј ϭ 9.6 Hz,
6Ј), 66.4, 73.3, 73.9, 75.7, 77.7, 78.6, 79.7, 80.3 (C-2, C-3, C-4, C- 1 H, H-2Ј), 5.63Ϫ5.82 (m, 1 H, CH2ϭCHϪCH2), 7.10Ϫ8.10 (m,
5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 99.7, 101.3, 101.4 (C-1, C-1Ј, CHPh), 15 H, HAr) ppm. 13C NMR (75.43 MHz, CDCl3): δ ϭ Ϫ3.3, Ϫ3.2
117.2 (CH2ϭCHϪCH2), 132.9 (CH2ϭCHϪCH2), 165.1 (CϭO) (CH3Si), 18.6, 18.7, 20.4, 20.5 (CH3 thexyl), 25.2 (Cq thexyl), 34.2
2860
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2853Ϫ2862

Solution Synthesis of Two Orthogonally Protected Lactosides
FULL PAPER
(CH thexyl), 62.0 (CH2ϭCHϪCH2), 68.9, 70.5, 72.8 (C-6, C-6Ј, 2 Loading 22 onto PS-DES Resin (30): PS-DES gel-type polystyrene
CH2Ph), 67.0, 69.0, 69.7, 71.6, 73.0, 79.0, 79.2, 81.0 (C-2, C-3, C- silane resin (300 mg, 0.29 mmol) was suspended in dry CH2Cl2 (2.9
4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 95.7, 101.1, 103.6 (C-1, C-1Ј, mL) and then 1,3-dichloro-5,5-dimethylhydantoin (28) (170 mg,
CHPh), 117.7 (CH2ϭCHϪCH2), 134.8 (CH2ϭCHϪCH2) ppm. 0.86 mmol) was added (to ensure complete chlorination of the sil-
C43H58O11Si (779.00) Calcd. C 66.30, H 7.50; found C 66.13, H
7.48.
ane linker, the concentration of the chlorinating agent should be
approximately 0.3 ). After 1.5 h, the polymer was filtered off and
washed with CH2Cl2 (3 ϫ 9 mL) and THF (2 ϫ 9 mL). The prod-
uct was transferred to a glass tray and dried in vacuo for 12 h to
give activated resin 29. The conversion of SiϪH units into SiϪCl
bonds was ascertained using IR spectroscopic analysis (DRIFT),
monitoring the disappearance of the typical stretch SiϪH at 2100
cmϪ1. The anchoring of the scaffold was performed by treating
resin 29 (250 mg) with a solution of scaffold 22 (610 mg, 0.7 mmol)
and imidazole (55 mg, 0.8 mmol) in dry CH2Cl2 (5 mL) under ar-
gon. After 24 h, the polymer was filtered off and washed with
CH2Cl2 (2 ϫ 15 mL), DMF/H2O (1:1, 2 ϫ 15 mL), THF/H2O (1:1,
2 ϫ 15 mL) and finally THF (2 ϫ 15 mL) to yield 30 (390 mg). 1H
NMR HR-MAS (400 MHz, CD2Cl2, selected data): δ ϭ 3.31 (br.
s, 2 H, H-5, H-5Ј), 3.47 (br. dd, 1 H, H-3Ј), 3.60Ϫ3.80 (m, 5 H, H-
2Ј, H-3, OCH3), 3.96 (br. d, 1 H, H-6Ј), 4.02Ϫ4.32 (m, 6 H, H-6Ј,
H-4Ј, H-4, H-6, CH2ϭCHϪCH2), 4.52Ϫ4.86 (m, 7 H, 2 CH2Ph,
CHHPh, H-1, H-1Ј), 5.11 (t, 1 H, H-2Ј), 5.18Ϫ5.30 (3 H, CH2ϭ
CHϪCH2, CHHPh), 5.51 (s, 1 H, CHPh), 5.86Ϫ6.00 (m, 1 H,
Benzyl (3-O-Allyl-2-O-benzoyl-4,6-O-benzylidene-β-
D-galactopyr-
anosyl)-(1Ǟ4)-2-O-benzyl-6-O-(thexyldimethylsilyl)-α-
D
-gluco-
pyranoside (27): Et3N (1.37 mL, 9.9 mmol) was added under argon
to a cooled (Ϫ5 °C) solution of 26 (430 mg, 0.54 mmol) in dry
CH3CN (5 mL). Benzoyl cyanide (1.62 mL of a 0.5  solution in
dry CH3CN) was added dropwise whilst stirring. After 24 h the
reaction mixture was diluted with CH2Cl2 and washed with satu-
rated aqueous NaHCO3; the organic layer was dried (Na2SO4), fil-
tered and concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/EtOAc, 7:3) to yield 27 (310 mg,
65%) as a clear oil. [α]2D0 ϭ ϩ29.6 (c ϭ 1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 0.08Ϫ0.12 (2 s, 6 H, CH3Si), 0.80Ϫ0.91
(4 s, 12 H, CH3 thexyl), 1.63 (m, 1 H, CH thexyl), 3.28Ϫ3.39 (m,
2 H, H-5, H-2), 3.49Ϫ3.61 (m, 4 H, H-6a, H-6b, H-4, H-5Ј), 3.66
(dd, J3Ј,4Ј ϭ 3.1, J3Ј,2Ј ϭ 10.3 Hz, 1 H, H-3Ј), 3.99Ϫ4.17 (m, 5 H,
CH2ϭCHϪCH2, H-3, H-6Јa, H-6Јb), 4.30 (br. s, 1 H, H-4Ј), 4.38
(d, J1,2 ϭ 3.9 Hz, 1 H, H-1), 4.42 (d, 1 H, CHHPh), 4.61 (d, Jgem ϭ
12.2 Hz, 1 H, CHHPh), 4.74 (m, 2 H, H-1Ј, CHHPh), 4.80 (d,
CH2ϭCHϪCH2) ppm. IR (DRIFT): ν˜max. ϭ 1745, 1240 cmϪ1
.
Jgem ϭ 11.9 Hz, 1 H, CHHPh), 5.12 (br. dd, 2 H, CH2ϭCHϪCH2),
5.54 (s, 1 H, CHPh), 5.61 (t, J2Ј,1Ј ϭ 9.5 Hz, 1 H, H-2Ј) 5.68Ϫ5.80
(m, 1 H, CH2ϭCHϪCH2), 7.10Ϫ7.60 (m, 20 H, HAr) ppm. 13C
NMR (75.43 MHz, CDCl3): δ ϭ 1.7, 2.1 (CH3Si), 14.9, 15.0, 20.6,
22.9 (CH3 thexyl), 30.0 (Cq thexyl), 61.4 (CH2ϭCHϪCH2), 69.1,
69.7, 70.6, 74.8 (C-6, C-6Ј, 2 CH2Ph), 66.8, 70.8, 73.2, 73.6, 75.6,
76.9, 79.0, 81.4 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 99.4,
101.1, 103.3 (C-1, C-1Ј, CHPh), 117.6 (CH2ϭCHϪCH2), 134.7
(CH2ϭCHϪCH2), 165.2 (CϭO) ppm. C50H62O12Si (883.11) Calcd.
C 68.00, H 7.08; found C 67.92, H 7.06.
Acknowledgments
We gratefully acknowledge financial support by Glaxo GSK
(Verona, Italy). S. C. is grateful to Glaxo GSK for a fellowship.
We also thank Dr. Carla Marchioro (Glaxo GSK) for MAS NMR
spectra and Dr. Alfredo Paio (Glaxo GSK) for his helpful and
fruitful suggestions.
[1]
A. Varki, Glycobiology 1993, 3, 97Ϫ130.
[2]
Benzyl (3-O-Allyl-2-O-benzoyl-4,6-O-benzylidene-β-
anosyl)-(1Ǟ4)-2-O-benzyl-3-O-(p-methoxybenzyl)-6-O-(thexyldi-
methylsilyl)-α- -glucopyranoside (3): p-Methoxybenzyl chloride (90
D-galactopyr-
L. A. Thomson, J. A. Ellman, Chem. Rev. 1996, 96, 555Ϫ600.
[3]
A. Nefzi, J. M. Ostresh, R. A. Houghten, Chem. Rev. 1997,
97, 449Ϫ472.
S. F. Oliver, C. Abell, Curr. Opin. Chem. Biol. 1999, 3,
299Ϫ306.
P. H. Seeberger, W.-C. Haase, Chem. Rev. 2000, 100,
4349Ϫ4393.
G.-J. Boons, Tetrahedron 1996, 52, 1095Ϫ1121 and references
cited therein.
D
[4]
µL, 0.67 mmol), NaH (16 mg, 0.67 mmol) and KI (110 mg,
0.67 mmol) were added under argon to a cooled (Ϫ30 °C) solution
of 27 (300 mg, 0.33 mmol) in dry DMF (3 mL). After 5 h, the reac-
tion mixture was quenched with methanol, diluted with CH2Cl2
and washed with H2O; the organic layer was dried (Na2SO4), fil-
tered and concentrated in vacuo. The residue was purified by flash
chromatography (toluene/EtOAc, 95:5) to yield 3 (161 mg, 48%) as
[5]
[6]
[7]
L. A. Marcaurelle, P. H. Seeberger, Curr. Opin. Chem. Biol.
2002, 6, 289Ϫ296 and references cited therein.
G. V. Coppa, O. Gabrielli, P. Giorgi, C. Catassi, M. P. Montan-
1
[8]
a yellow oil. [α]2D0 ϭ Ϫ56.5 (c ϭ 1, CHCl3). H NMR (300 MHz,
ari, P. E. Varaldo, B. L. Nichols, Lancet 1990, 335, 569Ϫ571.
CDCl3): δ ϭ 0.08Ϫ0.10 (2 s, 6 H, CH3Si), 0.78Ϫ0.89 (4 s, 12 H,
CH3 thexyl), 1.65 (m, 1 H, CH thexyl), 3.27 (br. dd, J2,3 ϭ 10.2 Hz,
1 H, H-2), 3.33 (br. d, J5,4 ϭ 9.5 Hz, 1 H, H-5), 3.45Ϫ3.85 (m, 9
H, H-4, 2 H-6, H-3Ј, H-5Ј, OCH3, CH2ϭCHϪCHH), 3.91 (br. dd,
1 H, CH2ϭCHϪCHH), 4.01Ϫ4.18 (m, 3 H, H-3, 2 H-6Ј), 4.30 (br.
s, 1 H, H-4Ј), 4.35Ϫ4.65 (m, 5 H, 3 CHHPh, CH2C6H4Ϫp-OMe),
4.74 (br. d, 1 H, H-1Ј), 4.78 (br. d, J1,2 ϭ 3.8 Hz, 1 H, H-1), 4,79
(d, Jgem ϭ 12.3 Hz, 1 H, CHHPh), 5.07Ϫ5.30 (m, 2 H, CH2ϭ
CHϪCH2), 5.55 (s, 1 H, CHPh), 5.61 (t, J2Ј,1Ј ϭ J2Ј,3Ј ϭ 9.6 Hz, 1
H, H-2Ј), 5.67Ϫ5.78 (m, 1 H, CH2ϭCHϪCH2), 7.00Ϫ8.10 (m, 24
H, HAr) ppm. 13C NMR (75.43 MHz, CDCl3): δ ϭ Ϫ4.0, Ϫ2.3
(CH3Si), 18.8, 18.9, 20.1, 20.2 (CH3 thexyl), 29.6 (Cq thexyl), 34.0
(CH thexyl), 55.5 (OCH3), 61.1 (CH2ϭCHϪCH2), 69.0, 69.5, 71.4,
75.0, 75.2 (2 CH2Ph, C-6, C-6Ј, CH2C6H4-p-OMe), 66.0, 73.1, 74.8,
74.2, 76.4, 79.2, 79.8, 80.0 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-
5Ј), 99.5, 101.3, 103.0 (C-1, C-1Ј, CHPh), 117.8 (CH2ϭCHϪCH2),
132.5 (CH2ϭCHϪCH2), 165.6 (CϭO) ppm. C59H73O13Si (1018.29)
Calcd. C 69.59, H 7.23, found C 69.74, H 7.24.
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