Novel approaches for the synthesis and activation of thio- and selenoglycoside donors

Article abstract of DOI:10.1021/jo070670o

(Chemical Equation Presented) Alkyl thio-, phenyl seleno-, and phenyl thioglycosides can be prepared through short synthetic sequences based on the generation of glycosyl iodides as versatile intermediates. In addition, a novel cheap combined system (stoichiometric NBS and catalytic Bi(OTf)₃) has been developed for rapid and efficient activation of a wide variety of thio- and selenoglycoside donors.

Full text of DOI:10.1021/jo070670o

Novel Approaches for the Synthesis and Activation of Thio- and
Selenoglycoside Donors
Silvia Valerio, Alfonso Iadonisi,* Matteo Adinolfi, and Alessandra Ravida`†
Dipartimento di Chimica Organica e Biochimica, UniVersita` degli Studi di Napoli Federico II,
Via Cynthia 4, I-80126 Napoli, Italy
iadonisi@unina.it
ReceiVed April 2, 2007
Alkyl thio-, phenyl seleno-, and phenyl thioglycosides can be prepared through short synthetic sequences
based on the generation of glycosyl iodides as versatile intermediates. In addition, a novel cheap combined
system (stoichiometric NBS and catalytic Bi(OTf)3) has been developed for rapid and efficient activation
of a wide variety of thio- and selenoglycoside donors.
Introduction
substoichiometric or excess amounts of harsh and sensitive
acidic reagents. In addition, reactions can be lengthy, and
undesired anomeric mixtures are occasionally observed. Re-
cently, a mild thioglycosidation promoter (MoO2Cl2) was found
to be efficient in catalytic amounts, although use of thiols and
lengthy reactions were still necessary.17 These problems can
be circumvented for alkyl thioglycosides by exploiting an
alternative synthetic scheme which contemplates the generation
of an S-glycosyl isothiouronium intermediate from a peracety-
lated glycosyl bromide and thiourea18 and the subsequent
S-alkylation in the presence of a mild base and an appropriate
alkyl halide. In another related approach, the generation of the
anomeric isothiouronium intermediate is achieved by coupling
a peracetylated sugar and thiourea in presence of an excess
Thioglycosides are broadly used as glycosyl donors in
oligosaccharide synthesis. Their usefulness is evidenced by the
numerous activation protocols reported over the years,1,2 and
their prevalent employment in recently developed procedures
for the one-pot assemblage of oligosaccharide fragments.2,3
Important advantages of such donors are the specific activation
conditions under the agency of “soft” promoters and the stability
to the wide range of conditions typically adopted in manipulating
the saccharidic functionalities. Anomeric thio groups can thereby
act themselves as temporary protecting groups. Alkyl- and aryl
thioglycosides are more routinely prepared by treating the
corresponding peracetylated precursors with the proper thiol or
thiotrimethylsilane in the presence of a Lewis acid.4-16 These
procedures suffer from the use of malodorous agents and
(9) Nanbiar, S.; Daueble, J. F.; Doyle, R. J.; Taylor, K. G. Tetrahedron
Lett. 1989, 30, 2179-2182.
† Current address: Centre for BioAnalytical Sciences, Dublin City University,
Glasnevin, Dublin 9, Ireland.
(1) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205.
(2) Code´e, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft,
H. S.; van der Marel, G. A. Chem. Soc. ReV. 2005, 34, 769-782.
(3) Zhang, Z.; Ollman, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734-753.
(4) Ferrier, R. J.; Furneaux, R. H. Methods Carbohydr. Chem. 1980, 8,
251-253.
(5) Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981, 93,
C6-C9.
(6) Lo¨nn, H. Carbohydr. Res. 1985, 139, 105-114.
(7) (a) Pozsgay, V.; Jennings, H. J. Tetrahedron Lett. 1987, 28, 1375-
1376. (b) Pozsgay, V.; Jennings, H. J. J. Org. Chem. 1988, 53, 4042-
4051.
(10) Kihlberg, J. O.; Leigh, D. A.; Bundle, D. R. J. Org. Chem. 1990,
55, 2860-2863.
(11) Das, S. K.; Roy, N. Carbohydr. Res. 1996, 296, 275-277.
(12) Olsson, L.; Kelberlau, S.; Jia, Z. J.; Fraser-Reid, B. Carbohydr. Res.
1998, 314, 273-276.
(13) Ding, Y. Synth. Commun. 1999, 29, 3541-3546.
(14) Tai, C.-A.; Kulkarni, S. S.; Hung, S.-C. J. Org. Chem. 2003, 68,
8719-8722.
(15) Das, S. K.; Roy, J.; Reddy, K. A.; Abbineni, C. Carbohydr. Res.
2003, 338, 2237-2240.
(16) Agnihotri, G.; Tiwari, P.; Misra, A. K. Carbohydr. Res. 2005, 340,
1393-1396.
(17) Weng, S.-S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8, 5633-
5636.
(18) Ibatullin, F. M.; Selivanov, S. I.; Shavva, A. G. Synthesis 2001,
419-422.
(8) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand. 1989, 43, 471-475.
10.1021/jo070670o CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/03/2007
J. Org. Chem. 2007, 72, 6097-6106
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Valerio et al.
SCHEME 1. Synthesis of Alkyl Thioglycosides via Thiouronium Intermediates Generated from Glycosyl Iodides
amount of a strong Lewis acid such as BF3·OEt2.19 Very
recently, peracetylated glycosyl bromides were again adopted
in another access to thioglycosides based on the preliminary
generation of the nucleophilic thiolate by reduction of a suitable
disulfide with activated zinc.20
Phenyl selenoglycosides are representing another class of
useful glycosyl donors activable by “soft” promoters.21-22
Analogous to thioglycosides, they are mostly prepared by acid
activation of peracetylated sugars in the presence of phenylse-
lenol generated “in situ” by a laborious procedure.21 Another
protocol relies on the generation of the phenylselenolate
anion by “in situ” reduction of phenyldiselenide with activated
zinc and its subsequent nucleophilic attack on glycosyl bro-
mides.20 Alternatively, InI can be used to mediate the same
transformation, although a different anomeric profile for the
products is observed as a consequence of a different reaction
mechanism.23
metric excess of I2 and triethylsilane (1.4 equiv each) in
refluxing dichloromethane.27 These reactions are extremely fast,
with TLC analysis generally displaying their completion
within 5 min. After a simple extractive workup, anomeric
iodides can be recovered contaminated only by a triethylsilane-
derived byproduct (NMR), which was found not to be detri-
mental for several subsequent synthetic elaborations.27 The
availability of this fast protocol spurred us to examine the
feasible use of the glycosyl iodides thus obtained as intermedi-
ates toward the generation of thio- and selenoglycoside
donors.
In a first approach, the generation of thioalkyl glycosides via
thiouronium salts was examined (Scheme 1). Crude iodides
obtained from I2/Et3SiH system were treated with a slight excess
of thiourea in acetonitrile at 60 °C. After 10-25 min, TLC
analysis displayed the consumption of the starting material and
the generation of a polar product. It should be noted that
refluxing conditions are needed for the analogous process to
be accomplished at a comparable rate starting from glycosyl
bromides.18 Direct addition of a suitable alkylating agent (EtI,
MeI, or BrCH2(CH2)8CHdCH2) and triethylamine at room
temperature led to the quick generation of the corresponding
thioglycosides (10-15 min were generally sufficient with EtI
and MeI). Concentration of the mixture and chromatographical
purification afforded a variety of thioalkyl glycosides in a good
overall yield as shown in Table 1. The whole sequence required
one extractive workup and a single chromatographical purifica-
tion and took less than 25 min for each step. In all cases, 1,2-
trans thioglycosides largely predominated, and they were easily
separated from the minor anomer. The process proved efficient
with a variety of saccharidic precursors and alkylating agents.
Notably, the procedure was also applicable to the perbenzoylated
precursor 3 (entry 3), which is reacting sluggishly in standard
Lewis acid promoted procedures,4 and the partially benzylated
derivative 7 (entry 7), which could be converted into the
corresponding iodide at a very low temperature (-20 °C) with
a reduced amount of I2 and triethylsilane (0.6 and 0.9 equiv,
respectively). Higher temperatures led to decomposition of the
saccharidic precursor, whereas use of TMSI as anomeric
iodinating agent was reported for the analogous substrate to work
at 0 °C in 2 h.28 Only in the synthesis of the 2-O-benzylated
thioglycoside 15 was the product obtained with predominance
of the 1,2-cis anomer (Table 1, entry 7). Expectedly, the
procedure was also compatible with 6-deoxy sugars (entries 5
and 6) and disaccharides (entry 8). Long thioalkyl chains (entry
Results and Discussion
1. Synthesis of Thio- and Selenoglycoside Donors via
Glycosyl Iodides. In the first part of this paper, we describe
the kinetic advantages associated with the use of glycosyl iodides
as precursors of thioalkyl-, thiophenyl-, and selenophenylgly-
cosides. In a very recent paper by Field and co-workers glycosyl
iodides were shown to be useful intermediates for the
synthesis of peracetylated ethyl or methyl thioglycosides, and
an efficient “one-pot” procedure from unprotected sugars was
developed.24 This sequence was based on initial fast peracety-
lation of the sugar with catalytic iodine and acetic anhydride,25
subsequent anomeric iodination by addition of stoichiometric
iodine and hexamethyldisilane,26 and final installation of an
anomeric thioalkyl group by addition of the proper disulfide or
thiol. The overall procedure requires just one extractive workup
and a single chromatographical purification. While the acety-
lation step is extremely fast, both the iodination and the
thioglycosidation step can take several hours. Recently, we have
shown that glycosyl iodides can be readily prepared from
peracetylated sugars by treatment with a moderate stoichio-
(19) Ibatullin, F. M.; Shabalin, K. A.; Ja¨nis, J. V.; Shavva, A. G.
Tetrahedron Lett. 2003, 44, 7961-7964.
(20) Mukherjee, C.; Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006,
47, 441-445.
(21) (a) Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32, 4435-4438.
(b) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269-3276.
(22) Zuurmond, H. M.; van der Meer, P. H.; van der Klein, P. A. M.;
van der Marel, G. A.; van Boom, G. A. J. Carbohydr. Chem. 1993, 12,
1091-1103.
(23) Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006, 47, 2345-
2348.
(24) Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.; Field, R. A.
J. Org. Chem. 2004, 69, 7758-7760.
(25) Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11753-
11766.
(27) (a) Adinolfi, M.; Iadonisi, A.; Schiattarella, M.; Ravida`, A.
Tetrahedron Lett. 2003, 44, 7863-7866. (b) For an application of these
intermediates, see: Adinolfi, M.; Iadonisi, A.; Pezzella, A.; Ravida`, A.
Synlett 2005, 1848-1852.
(28) (a) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2002, 4, 2039-2042.
(b) Lam, S. N.; Gervay-Hague, J. Carbohydr. Res. 2002, 337, 1953-
1965.
(26) Kartha, K. P. R.; Field, R. A. Carbohydr. Lett. 1998, 3, 179-
182.
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Synthesis and ActiVation of Thio- and Selenoglycoside Donors
TABLE 1. Synthesis of Alkyl Thioglycosides from 1-O-Acetylated Precursors (See Scheme 1)
a EtI as the alkylating agent. b BrCH2(CH2)8CHdCH2 as the alkylating agent. c Iodination step at -20 °C (see text and the Experimental Section).
8) could be attached onto the anomeric position even though
several hours were needed in this case for the final S-alkylation
step.
the corresponding diselenide or disulfide precursors with a
stoichiometric amount of sodium borohydride in ethanol29 or
acetonitrile (Scheme 2) without working under inert atmosphere.
Subsequent addition of these mixtures to the crude iodides
resulted in the formation of the corresponding seleno- and thio-
phenylglycosides in moderate to high yields and excellent stereo-
control (Table 3). Less than 1 h was generally sufficient to
perform the whole procedure without resorting to high tempera-
tures in the final substitution step as a recently reported approach
based on glycosyl bromides.20 Interestingly, the N-phtalimido
precursor 4 gave only R-glycosides in both cases, albeit in
moderate yield (Table 3, entries 5 and 6), and in these cases
only acetonitrile served well as the solvent. These latter results
are quite unexpected, as the bulky phtalimido group is known
to induce â-orientation in thio- and selenoglycosidations even
in approaches affording high R-selectivity with other saccharidic
precursors.23 Complete â-selectivity was instead observed in
other cases even when a precursor devoid of a participating 2-O-
acyl group was used (Table 3, entries 7 and 8).
The analogous synthetic scheme was then also pursued
starting from unprotected saccharidic precursors by adding the
aforementioned acetylation step under Field’s conditions
(catalytic iodine and a slight stoichiometric excess of acetic
anhydride)25 at its beginning (Table 2). After completion,
anomeric iodination was conducted by simply adding
dichloromethane, a further amount of iodine (up to overall
1.4 equiv), and triethylsilane (1.4 equiv) to the reaction
vessel and heating the mixture to reflux. In all cases, the
reactions proceeded in high yields and the acetic acid gene-
rated in the first step did not slow appreciably the conver-
sions. After an extractive workup, crude iodides were then sub-
mitted to the analogous conditions previously shown in
Scheme 1.
Reactivity of glycosyl iodides was also examined in the
generation of phenyl seleno- and phenyl thioglycosides,
which are broadly used in oligosaccharide synthesis but
not accessible via thiouronium intermediates. In preliminary
tests, we observed that phenylselenolate and phenylthiolate
anions can be quickly generated (10-15 min) by treating
On the other hand, this protocol of phenyl selenoglycosidation
was not very efficient when starting from the peracetylated
(29) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697-
2699.
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Valerio et al.
TABLE 2. Synthesis of Alkyl Thioglycosides from Unprotected
Precursors (See Text and Scheme 1)
TABLE 3. Synthesis of Phenyl Seleno- and Phenyl Thioglycosides
from 1-O-Acetylated Precursors (See Scheme 2)
a MeI as the alkylating agent. b EtI as the alkylating agent.
SCHEME 2. Synthesis of Phenyl Seleno- and Phenyl
Thioglycosides
laboratories. Softer Lewis acids have been reported as
copromoters with N-iodosuccinimide in occasional
examples.31,32
CHART 1
Due to the cost of N-iodosuccinimide, some attempt has
been made for using N-bromosuccinimide as a much cheaper
stoichiometric component of the activation system. Actually,
the sole NBS can activate reactive thioglicosides from
deoxysugars,33 while a suitable copromoter is necessary to
achieve a time-effective activation of ordinary sugars. For
example, Kusumoto reported the quick activation of armed
and disarmed thioglycosides by adopting several strong acid
salts in substoichiometric amounts (0.5 equiv) together
manno precursor 28 (Chart 1), as in acetonitrile the mixture of
anomeric selenoglycosides was obtained in average yield
together with the inseparable orthoester-like product 29
(Chart 1), whereas ethyl orthoester 30 was the predominant
product in EtOH. Attempted use of alternative solvents did not
lead to improved results.
2. Activation of Thio- and Selenoglycosides by NBS/Bi-
(OTf)3. Having in our hands efficient procedures to access a
variety of thio- and selenoglycosides, the donor ability of these
compounds was surveyed in test glycosidations. Thio- and
selenoglycosides can be activated by a wide range of pro-
moters of variable reactivity, and in all cases, at least a
stoichiometric reagent is needed.1,2,21,22 One of the most re-
liable procedures is represented by Van Boom’s protocol based
on the combined use of stoichiometric (often in excess
amounts) N-iodosuccinimide and catalytic triflic acid (or other
harsh Lewis acids such as trialkylsilyl triflates).22,30 The effi-
cacy of this approach is well witnessed by the numerous
successful applications reported over the years by several
(30) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 1331-1334.
(31) (a) Gelin, M.; Ferrie`res, V.; Plusquellec, D. Eur. J. Org. Chem.
2000, 1423-1431. (b) Pe´rion, R.; Leme´e, L.; Ferrie`res, V.; Duval, R.;
Plusquellec, D. Carbohydr. Res. 2003, 338, 2779-2792. (c) Jayaprakash,
K. N.; Faser-Reid, B. Org. Lett. 2004, 6, 4211-4214.
(32) Some examples of thio- and selenoglycoside activation based on a
single-electron-transfer (SET) mechanism have also been reported: (a)
Marra, A.; Mallett, J.-M.; Amatore, C.; Sinay¨, P. Synlett 1990, 572-574.
(b) Mehta, S.; Pinto, B. M. Carbohydr. Res. 1998, 310, 43-51. (c) van
Well, R. M.; Ka¨rkka¨inen, T. S.; Kartha, K. P. R.; Field, R. A. Carbohydr.
Res. 2006, 341, 1391-1397.
(33) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430-2434.
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Synthesis and ActiVation of Thio- and Selenoglycoside Donors
TABLE 4. Glycosidations of the Model Acceptor 31 with Thio- and Selenoglycosidesa
a General conditions: acceptor (1 equiv), donor (1.3 equiv), NBS (1.3 equiv), Bi(OTf)3 (0.1 equiv), DCE-dioxane, -30 to -25 °C for 30 min then
spontaneous warming if necessary. b 0.05 equiv of Bi(OTf)3 used. c 0.01 equiv of Bi(OTf)3 used.
with NBS (1.5 equiv) at -20 °C.34 In another protocol,
SCHEME 3. Glycosidation of Model Acceptor 31 with
Alkyl Thio-, Phenyl Thio-, and Phenyl Selenoglycosides
harsh and moisture-sensitive TMSOTf was used in catalytic
amounts (0.2 equiv) as copromoter with stoichiometric NBS in
reactions conducted at even lower temperatures (- 50 °C).35
In this latter paper, the electrophilic bromination of electron-
rich aromatic systems was observed as a feasible side
process.
In recent years, we have been interested in the development
of glycosidation protocols based on moisture-stable and easy
to handle Lewis acid promoters. Along this line, we have very
recently disclosed the high reactivity of bismuth(III) triflate
which can activate glycosyl trihaloacetimidates at rates
comparable to those of strong standard promoters.36 This
behavior spurred us to investigate the reactivity of this salt in
other glycosidation approaches. The interest was thus focused
on the combined NBS/Bi(OTf)3 system which appeared of
practical value due to the use of cheap and easily storable
reagents. A preliminary screening of conditions evidenced that
disarmed thioglycosides can be activated in dichloroethane at
temperatures as low as -30 °C by a catalytic amount of Bi-
(OTf)3 (added as a solution in dioxane). Having established
suitable conditions of activation, a wide variety of thio- and
selenoglycosides were coupled with the model acceptor 31
(Scheme 3).
(34) (a) Fukase, K.; Hasuoka, A.; Kusumoto, S. Tetrahedron Lett. 1993,
34, 2187-2190. (b) Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.;
Kusumoto, S. Tetrahedron 1995, 51, 4923-4932.
(35) Qin, Z. H.; Li, H.; Cai, M. S.; Li, Z. J. Carbohydr. Res. 2002, 337,
31-36.
(36) Adinolfi, M.; Iadonisi, A.; Ravida`, A.; Valerio, S. Tetrahedron Lett.
2006, 47, 2595-2599.
A number of 2-O-linked disaccharides could be prepared in
high yields adopting glycosyl donors from glucose, galactose,
N-phtalimidoglucosamine, mannose, and rhamnose (Table 4).
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Valerio et al.
TABLE 5. Glycosidations of the Model Acceptors 42 and 43 with Thio- and Selenoglycosidesa
a General conditions: acceptor (1 equiv), donor (1.3 equiv), NBS (1.3 equiv), Bi(OTf)3 (0.1 equiv), DCE-dioxane, -30 to -25 °C for 30 min then
spontaneous warming if necessary. b 0.05 equiv of Bi(OTf)3 used.
Reaction times generally did not exceed 1 h, and in some cases
a few minutes were sufficient. The amounts of bismuth(III)
triflate could be reduced (from 0.1 to 0.01 equiv) when
benzylated armed donors were used in place of the peracylated
counterparts (Table 4, entries 13-16). Predominance of R-linked
anomers was expectedly obtained in absence of participating
groups in the donors, reasonably due to the R-directing ability
of the dioxane cosolvent (Table 4, entries 13-16).37 Further
experiments were then conducted with other model acceptors
(42 and 43, Table 5) of differentiated reactivity, and rewarding
results were obtained in almost all cases. Interestingly,
glycosidation of the primary acceptor 43 with the acetylated
glucosyl donor 21 proceeded in low yield (Table 5, entry 3),
the 6-O-acetylated acceptor being obtained as the predominant
product (55% yield) arising from an acetyl transfer from the
donor.38
donor with the secondary acceptor 31 (Table 4, entry 14). In
an attempt to improve this selectivity, and concomitantly
to test the compatibility of the approach with acid-labile
functionalities, 6-O-tritylated donors 49 and 50 (Table 6) were
prepared from the corresponding 6-O-acetylated precursor 15
via Zemplen deacetylation and standard tritylation in
pyridine. Indeed, installation of sterically bulky groups at the
6-OH of glycosyl donors represents a known option to
improve the R-selectivity of glycosidations with a variety of
glycosyl donors.39 As a matter of fact, both 49 and 50
coupled with 43 to afford disaccharides 51 and 52 in high
yields and with a sensible improvement of selectivity (Table 6,
entries 1 and 2). Interestingly, no electrophilic aromatic bro-
mination35 of the electron-rich dimethoxytrityl group was
detected by MS analysis of the disaccharide anomers 52
deriving from donor 50. The compatibility of the acid-labile
trityl group was also confirmed in the coupling of 49 with the
less reactive secondary acceptor 31 (Table 6, entry 3) to afford
the R-linked disaccharide 53 in satisfying yield and high
stereocontrol.
This undesired process was absent in the case of a benzoylated
glucosyl donor (Table 5, entry 4) which afforded a markedly
higher yield. The coupling of primary acceptor 43 with donor
26, devoid of a participating group at O-2, proceeded in excellent
yield but with modest R-selectivity (entry 5), whereas an
excellent R-selectivity had been observed in coupling the same
(39) For some examples, see: (a) Tanaka, H.; Sakamoto, H.; Sano, A.;
Nakamura, S.; Nakajima, M.; Hashimoto, S. Chem. Commun. 1999, 1259-
1260. (b) Houdier, S.; Vottero, P. J. A. Carbohydr. Res. 1992, 232, 349-
352. (c) Boons, G.-J.; Bowers, S.; Coe, D. M. Tetrahedron Lett. 1997, 38,
3773-3776. (d) Fukase, K.; Nakai, Y.; Kanoh, T.; Kusumoto, S. Synlett
1998, 84-87. (e) Adinolfi, M.; Iadonisi, A.; Schiattarella, M. Tetrahedron
Lett. 2003, 44, 6479-6482.
(37) Demchenko, A.; Stauch, T.; Boons. G. J. Synlett 1997, 818-
820.
(38) Nakada, T.; Berces, A.; Whitfield, D. M. J. Org. Chem. 1999, 64,
9030-9045.
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Synthesis and ActiVation of Thio- and Selenoglycoside Donors
TABLE 6. Glycosidations with 6-O-Tritylated Donors 49 and 50a
a General conditions: acceptor (1 equiv), donor (1.3-1.4 equiv), NBS (1.3 equiv), Bi(OTf)3 (0.1 equiv), DCE-dioxane, -15 °C for 30 min then spontaneous
warming if necessary.
3.48 (1H, m, H-5), 2.70-2.56 (2H, m, -SCH2-), 2.15, 2.11, 2.07,
2.05, 2.04 (×2), 1.97 (21H, 7s, -COCH3), 2.10-1.20 (16H, m,
alkyl chain methylenes); 13C NMR (CDCl3, 75 MHz) δ 170.2 (×2),
170.1, 170.0, 169.6, 169.5, 169.0, 139.1, 114.1, 101.0, 83.4, 76.2,
73.7, 70.9, 70.6, 70.3, 69.0, 66.5, 62.2, 60.7, 33.7, 30.2, 29.6, 29.3,
29.0, 28.8, 20.7, 20.5; [R]25D -24.2 (c 1.0, CHCl3); MS (MALDI-
TOF) calcd for (C37H56O17SNa+) 827. 31, found 827.2. Anal. Calcd
for C37H56O17S: C, 55.21; H, 7.01. Found: C, 55.33; H, 7.21.
Preparation of Thioalkyl Glycoside 15 from Partially Ben-
zylated Precursor 7. I2 (56 mg, 0.22 mmol) and Et3SiH (53 µL,
0.33 mmol) were sequentially added at -20 °C to a solution of 7
(198 mg, 0.37 mmol) in DCM (1 mL). After the consumption of
the starting material (ca. 30 min, TLC analysis), the mixture was
worked up as described in the previous paragraph. The crude
glycosyl iodide was then elaborated essentially following the
analogous protocol described above (the generation of thiouronium
intermediate took less than 10 min, whereas the final alkylation
step took ca. 20 min).
Ethyl 2,3,4-tri-O-benzyl-6-O-acetyl-1-thio-R/â-D-glucopyra-
noside (15): 1H NMR (CDCl3, 300 MHz) δ 7.00-7.00 (Ar), 5.38
(1H, d, J1,2 ) 5.4 Hz, H-1 R), 5.00-4.50 (benzyl protons), 4.48
(1H, d, J1,2 ) 9.9 Hz, H-1 â), 4.40-4.15 (3H, m, H-5, H2-6), 3.90
(1H, t, J ) 9.6 Hz, H-3 R), 3.80 (1H, dd, H-2 R), 3.60-3.40 (m,
H-4, H-5 â and H-3 â), 2.80-2.45 (2H, m, SCH2CH3 â), 2.64-
2.45 (2H, m, SCH2CH3 R), 2.04 (3H, -COCH3 â), 2.02 (3H,
-COCH3 R), 1.33 (3H, t, J ) 7.5 Hz, SCH2CH3 â), 1.29 (3H, t, J
) 7.5 Hz, SCH2CH3 R); 13C NMR (CDCl3, 75 MHz) δ 170.4,
138.4, 137.7, 137.6, 128.3-127.5, 82.8, 82.3, 79.3, 76.9, 75.6, 74.8,
72.1, 68.8, 62.9, 23.5, 20.6, 14.6; MS (MALDI-TOF) calcd for
(C31H36O6SNa+) 559. 21, found 559.3. Anal. Calcd for
C31H36O6S: C, 69.38; H, 6.76. Found: C 69.21; H 6.84.
General Procedure for Preparation of Alkyl Thioglycosides
(from Unprotected Sugars). Iodine (98 mg, 0.38 mmol) was added
to a suspension of the unprotected sugar (1.00 g, 5.5 mmol) in acetic
anhydride (3.1 mL, 28.3 mmol) (caution: exhotermic reaction).
After completion of the acetylation (10-30 min), the mixture was
diluted with DCM (4 mL), and a further amount of I2 (1.82 g, 7.2
mmol) and triethylsilane (1.23 mL, 7.7 mmol) were sequentially
added. The mixture was refluxed until consumption of the per-
acetylated compound (less than 20 min, TLC) and then diluted with
DCM. The organic phase was sequentially washed with aq
In conclusion, in this paper we have shown that glycosyl
iodides, readily prepared by the I2/Et3SiH procedure, can be
converted into alkyl thio-, phenyl thio-, and phenyl selenogly-
cosides taking advantage of rapid, experimentally simple, and
efficient procedures. In addition, we have demonstrated that the
combined system NBS (stoichiometric)/Bi(OTf)3 (cat.) may
represent a cheap and efficient alternative procedure for the
activation of seleno- and thioglycoside donors under mild
conditions.
Experimental Section
General Procedure for Preparation of Thioalkyl Glycosides
(from Peracylated Precursors). To a solution of 1-O-acylated
sugar (5 mmol) in anhydrous DCM (10 mL) were added I2 (1.780
g, 7 mmol) and Et3SiH (1.12 mL, 7 mmol) (caution: exothermic
reaction). The system was refluxed until TLC analysis displayed
complete consumption of the starting material (5 min are generally
sufficient for peracetylated compounds, ca. 60 min are needed for
the perbenzoylated precursor 3). The mixture was then diluted with
DCM and the organic phase washed with aq sodium carbonate
containing sodium thiosulfate (this latter was added portionwise
until consumption of residual iodine in the organic phase). The
organic phase was then washed with water, dried, and concentrated.
Thiourea (570 mg, 7.5 mmol) was added to the crude residue, and
the mixture was suspended in acetonitrile (10 mL) and then heated
to 60 °C. After 10-25 min (ca. 60 min from the benzoylated
precursor 3), TLC analysis evidenced the consumption of the iodide
and the generation of a polar product. The vessel was cooled to rt,
and then alkyl iodide (10 mmol) and TEA (2.78 mL, 20 mmol)
were sequentially added. After 10-15 min, the reaction was
complete (TLC), and the mixture was concentrated under vacuum.
The residue was purified by flash silica gel chromatography
(petroleoum ether/ethyl acetate mixtures) to afford the alkyl
thioglycosides (see Tables 1 and 2 for yields).
1
Compound 16: oil; H NMR (CDCl3, 300 MHz) δ 5.80-5.70
(1H, m, -CHdCH2), 5.34 (1H, bd, J4,5 ) 2.7 Hz, H-4′), 5.20 (1H,
t, J ) 9.0 Hz, H-3), 5.08 (1H, dd, J1,2 ) 8.1 Hz, H-2′), 5.02-4.90
(4H, m, -CHdCH2, H-3′, H-2), 4.48 (1H, d, H-1′), 4.46 (1H, d,
J1,2 ) 10.2 Hz, H-1), 4.20-4.00 (4H, m, H2-6 and H2-6′), 3.88
(1H, bt, J5,6 ) 6.6 Hz, H-5′), 3.78 (1H, t, J ) 9.3 Hz, H-4), 3.66-
J. Org. Chem, Vol. 72, No. 16, 2007 6103

Valerio et al.
thiosulfate and aq carbonate. The organic phase was then dried and
concentrated under vacuum to yield the crude glycosyl iodide, which
was submitted to the synthesis of isothiuronium intermediate and
the final alkylation as illustrated above.
MS) and NBS (19 mg, 0.10 mmol) were added under argon. In
another vessel, a weighted amount of Bi(OTf)3 was coevaporated
with toluene and dried under vacuum for 30-60 min, and then
activated 4 Å molecular sieves were added under argon. The mixture
of donor, acceptor, and NBS was dissolved in anhydrous 1,2-
dichloroethane (0.9 mL) at low temperature (ice bath), while Bi-
(OTf)3 was dissolved at rt with dioxane (final concentration 20 mg/
mL). After being stirred for 15 min, the mixture of saccharidic
compounds was cooled to -30 °C, and then the solution of Bi-
(OTf)3 in dioxane was added (0.26 mL, 0.008 mmol). After 10
min, the reaction was complete (TLC analysis), and a few drops
of pyridine were added. The mixture was filtered on a short silica
gel plug and the residue from the organic phase chromatographed
on a silica gel column (eluant toluene/acetone 4:1) to yield
disaccharide 36 (56 mg, 96% yield). In the case of slower reactions,
the mixture was kept at -30 to -25 °C for 30 min, and then, if
necessary (TLC analysis), allowed to spontaneously raise until the
end of conversion.
General Procedure for Preparation of Phenyl Seleno- and
Phenyl Thioglycosides. To a mixture of phenyl diselenide (or
phenyl disulfide) (0.7 mmol) and NaBH4 (53 mg, 1.4 mmol) was
added ethanol (12 mL) or acetonitrile (5 mL). The mixture was
stirred until evolution of hydrogen ceased and then was shortly
heated at 50 °C to ensure completion of the reduction. The mixture
was then added to the crude glycosyl iodide (obtained from 1.0
mmol of precursor as described above). After the mixture was stirred
at rt for 5-60 min, acetic acid was added until neutrality, and the
mixture was diluted with DCM and washed with water. The aqueous
phase was re-extracted with DCM, and collected organic phases
were dried and evaporated under vacuum. The residue was purified
by silica gel flash chromatography (petroleum ether/ethyl acetate
mixtures).
Methyl 2,3,4,6-tetra-O-acetyl-â-D-gluco-pyranosyl-(1 f 2)-
3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (34): amor-
Phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-R-D-
glucopyranoside (24): foam; 1H NMR (CDCl3, 300 MHz) δ 7.90-
7.20 (Αr), 6.53 (1H, dd, J3,4 ) 9.3 Hz, J2,3 ) 12.0 Hz, H-3), 5.76
(1H, d, J1,2 ) 5.7 Hz, H-1), 5.10 (1H, dd, J4,5 ) 10.2 Hz, H-4),
1
phous solid; H NMR (CDCl3, 300 MHz) δ 7.50-7.20 (Ar), 5.55
(1H, s, benzylidene benzyl proton), 5.20 (1H, t, J ) 9.3 Hz, H-3′),
5.12 (1H, t, J ) 9.3 Hz, H-2′), 5.09 (1H, t, J ) 9.3 Hz, H-4′), 4.86
(1H, d, J1,2 ) 8.1 Hz, H-1′), 4.85-4.68 (2H, AB, -CH2Ph), 4.29
(1H, dd, J6eq,6ax ) 9.9 Hz, J6eq,5 ) 4.2 Hz, H-6eq), 4.28-4.10 (2H,
m, H2-6′), 4.00 (1H, t, J) 9.6 Hz, H-3), 3.82 (1H, td, J4,5 ) 9.6
Hz, H-5), 3.76-3.64 (3H, m, H-2, H-6ax, H-5′), 3.61 (1H, t, J )
9.3 Hz, H-4), 3.42 (3H, s, -OCH3), 2.09, 2.03, 2.00, 1.84 (12H,
4s, -COCH3); 13C NMR (CDCl3, 75 MHz) δ 170.5, 170.3, 169.4,
169.3, 138.3, 137.2, 128.9-126.0, 101.8, 101.3, 100.0, 82.2, 80.2,
75.0, 73.0, 71.8, 71.5, 69.0, 68.3, 62.0 (×2), 55.4, 20.6; [R]25D +9.5
(c 1.0, CHCl3); MS (MALDI-TOF) calcd for (C35H42O15Na+)
725.24, found 725.3. Anal. Calcd for C35H42O15: C, 59.82; H, 6.02.
Found: C, 59.70; H, 6.11.
4.89 (1H, dd, H-2), 4.70-4.60 (1H, m, H-5), 4.41 (1H, dd, J5,6a
)
4.8 Hz, J6a,6b ) 12.6 Hz, H-6a), 4.11 (1H, dd, J5,6b ) 1.2 Hz, H-6b),
2.08, 2.07, 1.88 (9H, 3s, 3 COCH3); 13C NMR (CDCl3, 300 MHz)
δ 170.6, 170.1, 169.3, 167.7, 167.1, 134.4, 133.3, 131.2, 129.0,
127.6, 123.8, 86.6, 70.4, 68.6, 67.6, 62.0, 53.7, 20.7; [R]25D +74.8
(c 1.0, CHCl3); MS (MALDI-TOF) calcd for (C26H25NO9SNa+)
550.11, found 550.1. Anal. Calcd for C26H25NO9S: C, 59.19; H,
4.78. Found: C, 59.10; H, 4.67.
Phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-seleno-R-
1
D-glucopyranoside (25): foam; H NMR (CDCl3, 300 MHz) δ
7.90-7.20 (Αr), 6.42 (1H, dd, J3,4 ) 8.7 Hz, J3,2 ) 11.7 Hz, H-3),
5.99 (1H, d, J1,2 ) 5.4 Hz, H-1), 5.09 (1H, dd, J4,5 ) 10.0 Hz,
H-4), 4.86 (1H, dd, H-2), 4.74-4.64 (1H, m, H-5), 4.40 (1H, dd,
J5,6a ) 4.8 Hz, J6a,6b ) 12.3 Hz, H-6a), 4.07 (1H, dd, J5,6b ) 2.1
Hz, H-6b), 2.06, 2.05, 1.86 (9H, 3s, 3 - COCH3); 13C NMR (CDCl3,
75 MHz) δ 170.4, 169.8, 169.1, 134.4, 133.5, 129.0, 128.6, 127.7,
84.4 (C-1), 69.9, 69.8, 67.9, 61.7, 54.0, 20.5; [R]25D +69.6 (c 1.0,
CHCl3); MS (MALDI-TOF) calcd for (C26H25NO9SeNa+) 598.06,
found 598.1. Anal. Calcd for C26H25NO9Se: C, 54.36; H, 4.39.
Found: C, 54.62; H, 4.18.
Methyl 2,3,4,6-tetra-O-benzoyl-â-D-glucopyranosyl-(1 f 2)-
3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (35): foam;
1H NMR (CDCl3, 300 MHz) δ 8.10-7.20 (Αr), 5.92 (1H, t, J)
9.9 Hz, H-3′), 5.75-5.67 (2H, m, H-4′, H-2′), 5.50 (1H, s,
benzylidene benzyl proton), 5.19 (1H, d, J1,2 ) 7.8 Hz, H-1′), 4.97
(1H, d, J1,2 ) 3.3 Hz, H-1), 4.74 (1H, dd, J5,6a ) 3.0 Hz, J6a,6b
)
12.0 Hz, H-6′a), 4.56-4.38 (2H, AB, -CH2Ph), 4.45 (1H, dd, J5,6b
) 5.7 Hz, H-6′b), 4.27 (1H, dd, J5,6eq ) 4.8 Hz, J6ax,6eq ) 10.2 Hz,
H-6eq), 4.20-4.15 (1H, m, H-5′), 3.93 (1H, t, J) 9.6 Hz, H-3),
3.81-3.76 (2Η, m, H-5, H-2), 3.72 (1Η, t, H-6ax), 3.54 (1H, t,
H-4), 3.38 (3Η, s, -OCH3); 13C NMR (CDCl3, 75 MHz) δ 166.0,
165.8, 165.2, 165.0, 138.4, 137.3, 133.5, 133.2-127.4, 127.2, 126.0,
102.3, 101.4, 100.3, 82.1, 80.7, 74.7, 73.1, 72.3, 72.0, 69.6,
Phenyl 2,3,4-tri-O-benzyl-6-O-acetyl-1-thio-â-D-glucopyrano-
1
side (26): H NMR (CDCl3, 300 MHz) δ 7.60-7.20 (Ar), 5.00-
4.55 (6H, CH2Ph), 4.68 (1H, d, J1,2 ) 9.9 Hz, H-1), 4.38 (1H, bd,
J6a,6b ) 12.3 Hz, H-6a), 4.20 (1H, dd, J5,6b ) 3.0 Hz, H-6b), 3.80-
3.70 (1H, m, H-5), 3.60-3.45 (3H, m, H-2, H-3, H-4), 2.06 (3H,
s, COCH3); 13C NMR (CDCl3, 75 MHz) δ 170.3, 138.0, 137.7,
137.4, 133.4, 131.8, 128.7, 127.4, 87.2, 86.5, 80.7, 77.3, 76.7, 75.6,
75.3, 74.8, 63.0, 20.6. [R]25D +14.1 (c 1, CHCl3); mp (MeOH) 69-
70 °C; MS (MALDI-TOF) calcd for (C35H36O6SNa+) 607.22, found
607.1. Anal. Calcd for C35H36O6S: C, 71.89; H, 6.21. Found: C,
72.06; H, 6.19.
69.1, 62.7, 62.0, 55.5; [R]25 +33.6 (c 0.90, CHCl3); MS
D
(MALDI-TOF) calcd for (C55H50O15Na+) 973.31, found 973.2.
Anal. Calcd for C55H50O15: C, 69.46; H, 5.30. Found: C, 69.51;
H, 5.39.
Methyl 2,3,4,6-tetra-O-acetyl-â-D-galacto-pyranosyl-(1 f 2)-
3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (36): oil; 1H
NMR (CDCl3, 300 MHz) δ 7.50-7.20 (Ar), 5.55 (1H, s, ben-
zylidene benzyl proton), 5.34 (1H, dd, J2,1 ) 8.1 Hz, J2,3 ) 10.5
Hz, H-2′), 5.37 (1H, bd, J3,4 ) 3.6 Hz, H-4′), 5.00 (1H, dd, H-3′),
4.85 (1H, d, J1,2 ) 3.6 Hz, H-1), 4.83-4.68 (2H, AB, -CH2Ph),
4.79 (1H, d, J) 7.8 Hz, H-1′), 4.28 (1H, dd, J5,6eq ) 4.5 Hz, J6eq,6ax
) 9.9 Hz, H-6eq), 4.14 (2H, d, J ) 6.3 Hz, H2-6′), 4.01 (1H, t, J)
9.3 Hz, H-3), 3.86-3.68 (4H, m, H-5, H-5′, H-2, H-6ax), 3.64 (1H,
t, H-4), 3.41 (3Η, s, -OCH3), 2.15, 2.04, 1.97, 1.83 (12H, 4s, 4 ×
-COCH3); 13C NMR (CDCl3, 75 MHz) δ 170.1 (×2), 169.9, 169.0,
138.1, 137.0, 128.6-125.7, 102.1, 101.1, 99.7, 82.0, 80.3, 76.4,
Phenyl 2,3,4-tri-O-benzyl-6-O-acetyl-1-seleno-â-D-glucopyra-
noside (27): 1H NMR (CDCl3, 300 MHz) δ 7.75-7.15 (Ar), 4.90-
4.50 (7H, CH2Ph and anomeric proton), 4.26 (1H, bd, J ) 12.0
Hz, H-6a), 4.28 (1H, dd, J5,6b ) 3.6 Hz, H-6b), 3.80-3.75 (1H, m,
H-5), 3.64-3.55 (3H, m, H-2, H-3, H-4), 1.98 (3H, s, COCH3);
13C NMR (CDCl3, 75 MHz) δ 170.1, 138.0, 137.7, 137.4, 137.2,
134.2, 128.5-127.4, 86.4, 82.4, 80.9, 76.3, 75.4, 74.8, 74.6, 62.7,
20.4; [R]25 +11.1 (c 1.0, CHCl3); mp (MeOH) 68-69 °C; MS
D
(MALDI-TOF) calcd for (C35H36O6SeNa+) 655.15, found 655.0.
Anal. Calcd for C35H36O6Se: C, 66.56; H, 5.74. Found: C, 66.29;
H, 5.67.
74.8, 70.9, 70.6, 68.8, 68.7, 66.8, 62.0, 61.4, 55.1, 20.4; [R]25
D
+10.3 (c 0.90, CHCl3); MS (MALDI-TOF) calcd for (C35H42O15-
Na+) 725.24, found 725.2. Anal. Calcd for C35H42O15: C, 59.82;
H, 6.02. Found: C, 59.59; H, 6.23.
General Procedure for Glycosidation with the NBS/Bi(OTf)3
System. Donor 22 (46 mg, 0.10 mmol) and acceptor 31 (30 mg,
0.08 mmol) were coevaporated three times in anhydrous toluene
(3 × 1 mL). The mixture was kept under vacuum for 30-60 min,
and then activated 4 Å acid washed molecular sieves (AW 300
Methyl 2,3,4,6-tetra-O-acetyl-R-D-mannopyranosyl-(1 f 2)-
3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (37): oil; 1H
6104 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis and ActiVation of Thio- and Selenoglycoside Donors
NMR (CDCl3, 300 MHz) δ 7.50-7.20 (Ar), 5.61 (1H, s, ben-
zylidene benzyl proton), 5.41 (1Η, dd, J3,2 ) 3.3 Hz, J3,4 ) 9.9
Hz, H-3′), 5.31 (1Η, dd, J1,2 ) 1.5 Hz, H-2′), 5.29 (1Η, t, J ) 9.9
Hz, H-4′), 4.97-4.75 (2H, AB, -CH2Ph), 4.95 (1H, bs, H-1′), 4.86
(1H, d, J1,2 ) 3.6 Hz, H-1), 4.32 (1H, dd, J5,6eq ) 4.5 Hz, J6ax,6eq
) 9.6 Hz, H-6eq), 4.28-4.20 (1H, m, H-5′),4.04 (1H, t, J) 9.6
Hz, H-3), 4.00 (1H, dd, J6a,6b ) 9.7, J6a,5 ) 4.8 Hz, H-6a′), 3.94-
3.80 (3H, m, H-6b′, H-5), 3.77 (1Η, t, H-6ax), 3.70 (1Η, t, H-4),
3.46 (3Η, s, -OCH3), 2.18, 2.08, 2.02, 2.00 (12H, 4xs, -COCH3);
13C NMR (CDCl3, 75 MHz) δ 170.6, 170.1, 169.7, 169.6, 138.1,
137.2, 129.0-126.0, 101.3, 97.1, 94.7, 82.5, 75.4, 74.5, 69.8, 69.0,
3.80 (2H, m, H-5 and H-5′), 3.78 (1H, bd, H-4′), 3.71 (1H, t, J )
10.6 Hz, H-6ax), 3.58-3.30 (4H, m, H-4, H-2, H2-6′), 3.43 (3Η,
s, -OCH3); 13C NMR (CDCl3, 75 MHz) δ 138.8 (×2), 138.7 (×2),
138.4, 137.8, 128.8-125.9, 101.2, 97.3, 94.9, 82.3, 78.8, 77.3, 75.9,
75.3, 74.9, 74.7, 73.9, 73.0, 72.8, 72.7, 68.9, 62.3, 55.0; MS
(MALDI-TOF) calcd for (C55H58O11Na+) 917.39, found 917.4.
Anal. Calcd for C55H58O11: C, 73.81; H, 6.53. Found: C, 73.58;
H, 6.38.
Methyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-â-D-glucopy-
ranosyl-(1 f 3)-2-O-acetyl-4,6-O-benzylidene-R-D-glucopyra-
noside (44): foam; 1H NMR (CDCl3, 300 MHz) δ 7.80-7.20 (Αr),
68.9, 68.5, 65.6, 62.2, 61.7, 55.5, 20.9, 20.6; [R]25 +51.5 (c 1.0,
5.74 (1H, dd, J ) 10.8 Hz, J ) 9.09 Hz, H-3′), 5.56 (1H, d, J1,2
)
D
CHCl3); MS (MALDI-TOF) calcd for (C35H42O15Na+) 725.24,
found 725.1. Anal. Calcd for C35H42O15: C, 59.82; H, 6.02.
Found: C, 59.96; H, 5.89.
8.4 Hz, H-1′), 5.52 (1H, s, benzylidene benzyl proton), 5.14 (1H,
dd, H-4′), 4.80 (1H, d, J1,2 ) 3.9 Hz, H-1), 4.65 (1H, dd, J2,3 ) 9.6
Hz, H-2), 4.33-4.18 (2H, m, H-3 and H-2′), 4.12 (1H, dd, J5,6a
)
Methyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-â-D-glucopy-
ranosyl-(1 f 2)-3-O-benzyl-4,6-O-benzylidene-R-D-glucopyra-
noside (38): foam; 1H NMR (CDCl3, 300 MHz) δ 7.80-6.80 (Αr),
5.77 (1H, t, 9.6 Hz, H-3′), 5.65 (1H, d, J1,2 ) 8.7 Hz, H-1′), 5.43
(1H, s, benzylidene benzyl proton), 5.17 (1H, t, J) 9.6 Hz, H-4′),
4.93 (1H, d, J1,2 ) 3.3 Hz, H-1), 4.51 (1H, dd, H-2′), 4.36-4.15
(5H, m, -CH2Ph, H-6eq, and H2-6′), 3.95-3.60 (5H, m, H-3, H-5,
H-6ax, H-5′, and H-2), 3.49 (1H, t, J ) 9.3 Hz, H-4), 3.41 (3Η, s,
-OCH3), 2.12, 2.04, 1.86 (9H, 3s, 3 -COCH3); 13C NMR (CDCl3,
75 MHz) δ 170.4, 170.1, 169.4, 138.2, 137.1, 134.1, 131.1, 128.9-
125.9, 123.4, 101.2, 99.9, 99.7, 82.1, 81.8, 76.0, 73.9, 71.9, 70.7,
4.2 Hz, J6a,6b ) 12.3 Hz, H-6′a), 3.91 (1H, dd, J5,6b ) 2.4 Hz, H-6′b),
3.79-3.70 (2H, m, H-5 and H-6ax), 3.65-3.55 (2H, m, H-4 and
H-5′), 3.30 (3Η, s, -OCH3), 2.01, 1.98, 1.92, 1.81 (12H, 4s, 4
-COCH3); 13C NMR (CDCl3, 75 MHz) δ 170.7, 170.2 (×2), 169.4,
137.1, 134.3, 131.2, 129.0, 128.2, 126.0, 125.3, 123.5, 101.3, 97.2,
97.0, 79.3, 74.8, 72.7, 71.6, 70.6, 68.9, 68.7, 62.0, 61.7, 55.2, 54.7,
20.7, 20.6, 20.4; [R]25D +43.0 (c 1.0, CHCl3); MS (MALDI-TOF)
calcd for (C36H39NO16Na+) 764.22, found 764.4. Anal. Calcd for
C36H39NO16: C, 58.30; H, 5.30. Found: C, 58.53; H, 5.56.
Methyl 2,3,4,6-tetra-O-acetyl-R-D-mannopyranosyl-(1 f 3)-
2-O-acetyl-4,6-O-benzylidene-R-D-glucopyranoside (45): foam;
1H NMR (CDCl3, 300 MHz) δ 7.40-7.20 (Ar), 5.55 (1H, s,
benzylidene benzyl proton), 5.33 (1Η, t, J ) 1.8 Hz, H-2′), 5.29
(1Η, d, H-1′), 5.26-5.18 (2Η, m, H-4′ and H-3′), 4.97 (1H, d, J1,2
) 3.6 Hz, H-1), 4.81 (1H, dd, J2,3 ) 9.9 Hz, H-2), 4.34-4.24 (2H,
m, H-6eq, H-3), 4.22-4.10 (3H, m, H-5′ and H2-6′), 3.86-3.68
(3H, m, H-4, H-5 and H-6ax), 3.37 (3H, s, -OCH3), 2.12, 2.10,
2.07, 2.02, 1.96 (15H, 5s, 5 × -COCH3); 13C NMR (CDCl3, 75
MHz) δ 170.7, 170.0, 169.8, 169.7, 169.6, 136.7, 128.9, 128.1 (×2),
126.0 (×2), 101.2, 97.5 (×2), 81.9, 72.0, 71.6, 69.1, 68.9, 68.7,
68.9, 68.8, 62.2, 62.1, 55.3, 54.5, 20.7, 20.5, 20.3. [R]25 +25.5
D
(c 1.0, CHCl3); MS (MALDI-TOF) calcd for (C41H43NO15Na+)
812.25, found 812.1. Anal. Calcd for C41H43NO15: C, 62.35; H,
5.49. Found: C, 62.46; H, 5.56.
Methyl 2,3,4-tri-O-acetyl-R-L-rhamnopyranosyl-(1 f 2)-3-O-
benzyl-4,6-O-benzylidene-R-D-glucopyranoside (39): oil; 1H NMR
(CDCl3, 300 MHz) δ 7.50-7.20 (Ar), 5.81 (1H, s, benzylidene
benzyl proton), 5.40-5.35 (2Η, H-3′, H-2′), 5.08 (1Η, t, J ) 9.6
Hz, H-4′), 4.98 (1Η, bs, H-1′), 4.89-4.78 (3H, -CH2Ph and H-1),
4.29 (1H, dd, J5,6eq ) 3.6 Hz, J6ax,6eq ) 9.3 Hz, H-6eq), 4.10-3.97
(2H, m, H-5′ and H-3), 3.88-3.81 (1H, td, J ) 9.6 Hz, H-5), 3.75
(1Η, t, J ) 10.2 Hz, H-6ax), 3.68 (1H, dd, J1,2 ) 3.6 Hz, H-2),
3.62 (1H, t, H-4), 3.42 (3Η, s, -OCH3), 2.13, 2.07, 2.01 (9H, 3s,
-COCH3), 1.23 (1H, d, J ) 6.3 Hz, H3-6′); 13C NMR (CDCl3, 75
MHz) δ 170.0, 169.8, 169.7, 138.2, 137.2, 128.9, 128.3, 128.2,
127.6, 126.0, 101.3, 100.1, 99.6, 82.0, 80.7, 77.2, 75.3, 71.0, 69.6,
69.0, 66.9, 62.2, 55.1, 20.8, 20.7, 17.5; [R]25D -8.6 (c 1.0, CHCl3);
MS (MALDI-TOF) calcd for (C33H40O13Na+) 667.24, found 667.2.
Anal. Calcd for C33H40O13: C, 61.48; H, 6.25. Found: C 61.32; H
6.20.
66.0, 62.2, 61.9, 55.3, 20.6; [R]25 +81.2 (c 1.0, CHCl3); MS
D
(MALDI-TOF) calcd for (C30H38O16Na+) 677.22, found 677.2.
Anal. Calcd for C30H38O16: C, 55.04; H, 5.85. Found: C, 54.93;
H, 5.99.
2,3,4,6-Tetra-O-acetyl-â-D-glucopyranosyl-(1 f 6)-1,2:3,4-O-
diisopropylidene-R-D-galactopyranose (46): foam; 1H NMR
(CDCl3, 300 MHz) δ 5.49 (1H, d, J1,2 ) 4.8 Hz, H-1), 5.22 (1H,
t, J) 9.3 Hz, H-3′), 5.09 (1H, t, H-4′), 5.01 (1H, dd, H-2′), 4.62
(1H, d, J1,2 ) 8.1 Hz, H-1′), 4.59 (1H, dd, J2,3 ) 2.4 Hz, J3,4 ) 8.1
Hz, H-3), 4.30-4.23 (2Η, m, H-2, H-6′a), 4.18-4.09 (2H, m, H-6′b,
H-4), 4.01 (1H, dd, J5,6a ) 3.6 Hz, J6a,6b ) 11.4 Hz, H-6a), 3.96-
3.88 (1H, m, H-5), 3.74-3.60 (2H, m, H-5′, H-6b), 2.07, 2.06,
2.01, 1.99 (4H, 4s, 4 -COCH3), 1.49, 1.43, 1.31 (×2) (12H, 3s,
isopropylidene methyls); 13C NMR (CDCl3, 75 MHz) δ 170.7,
170.3, 169.6, 169.4, 109.4, 108.7, 101.4, 96.2, 72.7, 71.7, 71.2,
71.0, 70.6, 70.4, 69.5, 68.5, 67.8, 61.9, 26.0, 25.9, 25.0, 24.3, 20.6;
Methyl 6-O-acetyl-2,3,4-tri-O-benzyl-R-D-glucopyranosyl-(1
f 2)-3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (40):
1
amorphous solid; H NMR (CDCl3, 300 MHz) δ 7.50-7.00 (Ar),
5.59 (1H, s, benzylidene benzyl proton), 5.06-4.51 (6H, 3 × AB,
-CH2Ph), 4.90 (1H, d, J ) 3.6 Hz, H-1), 4.87 (1H, d, J ) 3.9 Hz,
H-1′), 4.32 (1H, dd, J6eq,5 ) 4.5, J6eq,6ax ) 9.9 Hz, H-6eq), 4.24-
4.18 (1H, m, H-5′), 4.16-4.08 (2H, m, H-3′ and H-3), 4.15-3.98
(2H, m, H2-6′), 3.92-3.80 (2H, m, H-2′ and H-5), 3.76 (1H, t, J )
9.9 Hz, H-6ax), 3.66 (1H, t, J ) 9.3 Hz, H-4′), 3.56 (1H, dd, J2,3
) 9.6 Hz, H-2), 3.52 (1H, t, J ) 9.9 Hz, H-4), 3.46 (3H, s, -OCH3),
1.97 (3H, s, -COCH3); 13C NMR (CDCl3, 75 MHz) δ 170.5 138.6,
138.2 (×2), 137.9,137.3, 128.6-125.9, 101.2, 97.1, 94.2, 82.5, 81.9,
79.2, 77.1, 76.7, 75.6(×2), 74.9, 74.4, 72.9, 68.9, 68.6, 62.4, 62.2,
54.9, 20.7; [R]25D +39.5 (c 1.0, CHCl3); MS (MALDI-TOF) calcd
for (C50H54O12Na+) 869.35, found 869.2. Anal. Calcd for
C50H54O12: C, 70.91; H, 6.43. Found: C, 71.11; H, 6.54.
[R]25 -52.8 (c 1.0, CHCl3); mp (EtOH) 139-140 °C; MS
D
(MALDI-TOF) calcd for (C26H38O15Na+) 613.21, found 613.3.
Anal. Calcd for C26H38O15: C, 52.88; H, 6.49. Found: C, 52.80;
H, 6.58.
2,3,4,6-Tetra-O-benzoyl-â-D-glucopyranosyl-(1 f 6)-1,2:3,4-
1
di-O-isopropylidene-R-D-galactopyranose (47): foam; H NMR
(CDCl3, 300 MHz) δ 8.10-7.20 (Αr), 5.91 (1H, t, J ) 9.6 Hz,
H-3′), 5.69 (1H, t, J ) 9.6 Hz, H-4′), 5.55 (1H, dd, J1,2 ) 7.8 Hz,
J2,3 ) 9.6 Hz, H-2′), 5.42 (1H, d, J1,2 ) 4.8 Hz, H-1), 5.05 (1H, d,
J1,2 ) 7.8 Hz, H-1′), 4.65 (1H, dd, J5,6a ) 3.3 Hz, J6a,6b ) 12.0 Hz,
H-6′a), 4.49 (1H, dd, J5,6b ) 5.1 Hz, J6a,6b ) 12.0 Hz, H-6′b), 4.43
(1H, dd, J3,2 ) 2.1, J3,4 ) 8.1, H-3), 4.25-4.15 (3H, m, H-2, H-4
and H-5′), 4.15-4.00 (2H, m, H2-6), 3.95-3.85 (1Η, m, H-5), 1.37,
1.24, 1.21, 1.20 (12H, 4s, isopropylidene methyls); 13C NMR
(CDCl3, 75 MHz) δ 166.1, 165.7, 165.2, 165.1, 133.3, 133.1, 133.0,
130.0-128.1, 109.2, 108.4, 101.2, 96.1, 73.0, 72.1, 71.7, 70.9, 70.5,
70.3, 69.7, 68.2, 67.5, 63.2, 25.8, 25.6, 24.8, 24.2; [R]25D -15.7 (c
1.0, CHCl3); MS (MALDI-TOF) calcd for (C46H46O15Na+) 861.27,
Methyl 2,3,4,6-tetra-O-benzyl-R-D-galactopyranosyl-(1 f 2)-
3-O-benzyl-4,6-O-benzylidene-D-glucopyranoside (41): amor-
1
phous solid; H NMR (CDCl3, 300 MHz) signals of R-anomer δ
7.60-7.00 (Ar), 5.53 (1H, s, benzylidene benzyl proton), 4.97 (1H,
d, J) 3.3 Hz, H-1′), 4.93 (1H, d, J) 3.3 Hz, H-1), 5.00-4.20
(-CH2Ph and H-6eq), 4.11 (1H, t, J) 9.6 Hz, H-3), 4.04 (1H, dd,
J2,3 ) 10.2 Hz, H-2′), 3.96 (1H, dd, J3,4 ) 2.4 Hz, H-3′), 3.95-
J. Org. Chem, Vol. 72, No. 16, 2007 6105

Valerio et al.
found 861.3. Anal. Calcd for C46H46O15: C, 65.86; H, 5.53.
Found: C, 65.98; H, 5.63.
4.32 (1H, dd, H-2), 4.06 (1H, bt, J5,6 ) 7.5 Hz, H-5), 3.97 (1H, t,
J ) 9.3 Hz, H-3′), 3.88-3.72 (4H, m, H-4′, H-5′, H2-6), 3.77 and
3.76 (6H, 2s, 2 × -OCH3), 3.67 (1H, dd, H-2′), 3.52 (1Η, bd,
J6a,6b ) 9.6 Hz, H-6′a), 3.22 (1H, bd, J5,6b ) 3.9 Hz, H-6′b),1.52,
1.48, 1.33 (×2) (12H, 3s, isopropylidene methyls); 13C NMR
(CDCl3, 75 MHz) δ 158.3, 145.0, 138.8, 138.5, 136.3, 135.9,
130.01-126.6, 113.0, 109.1, 108.5, 96.3 (×2), 85.6, 82.0, 80.0,
77.9, 77.8, 76.0, 74.9, 72.1, 70.8, 70.7, 70.5, 65.3, 62.0, 55.1, 26.1
(×2), 24.9, 24.6; MS (MALDI-TOF) calcd for (C60H66O13Na+)
1017.44, found 1017.5. Anal. Calcd for C60H66O13: C, 72.41; H,
6.68. Found: C, 72.49; H, 6.79.
6-O-Acetyl-2,3,4-tri-O-benzyl-D-glucopyranosyl-(1 f 6)-1,2:
3,4-di-O-isopropylidene-R-D-galactopyranose (48): oil; 1H NMR
(CDCl3, 300 MHz) signals of R anomer at δ 7.50-7.10 (Ar), 5.53
(1H, d, J1,2 ) 5.1 Hz, H-1), 5.10-4.50 (7H, -CH2Ph and H-3),
4.96 (1H, d, J1,2 ) 3.9 Hz, H-1′), 4.37-4.00 (5H, m, H-2, H-4,
H-5, H2-6′, H-3′), 3.98-3.90 (1H, m, H-5′), 3.82-3.44 (4H, m,
6-CH2, H-2′, H-4′), 2.03 (3H, s, -COCH3), 1.54, 1.46, 1.33, and
1.32 (12H, 4s, isopropylidene methyls); significant signals of the
â-linked disaccharide at δ 5.57 (1H, d, J1,2 ) 4.8 Hz, H-1), 4.47
(1H, d, J1,2 ) 8.1 Hz, H-1′), 2.04 (3H, s, -COCH3). 13C NMR
(CDCl3, 75 MHz) δ 170.8, 138.7, 138.5, 137.9, 137.7, 128.6-127.6,
109.4, 109.2, 108.6, 104.5 (C-1′ â), 97.3 (×2) (C-1 R and â), 97.0
(C-1′ R), 84.5, 81.8, 81.5, 79.8, 75.7, 75.0, 74.8, 74.3, 72.8, 72.4,
71.4, 70.8, 70.7, 70.6, 70.4, 70.0, 68.6, 67.3, 66.6, 65.8, 63.0, 24.9,
24.6, 24.4, 20.9; MS (MALDI-TOF) calcd for (C41H50O12Na+)
757.21, found 757.1. Anal. Calcd for C41H50O12: C, 67.01; H, 6.86.
Found: C, 67.29; H, 7.02.
Methyl 2,3,4-tri-O-benzyl-6-O-trityl-R-D-glucopyranosyl-(1 f
2)-3-O-benzyl-4,6-O-benzylidene-R-D-glucopyranoside (53): foam;
1H NMR (CDCl3, 300 MHz) δ 7.60-6.80 (Ar), 5.55 (1H, s,
benzylidene benzyl proton), 5.06 (1H, d, J1,2 ) 3.6 Hz, H-1), 5.00
(1H, d, J1,2 ) 3.3 Hz, H-1′), 5.00-4.30 (8H, 4 × AB, -CH2Ph),
4.31 (1H, dd, J6eq,6ax ) 9.6 Hz, J6eq,5 ) 3.0 Hz, H-6eq), 4.28-4.20
(1H, m, H-5′), 4.16-4.07 (2H, m, H-3 and H-3′), 3.97 (1H, dd,
J2,3 ) 9.6 Hz, H-2′), 3.94-3.85 (1H, m, H-5), 3.77 (2H, overlapped
t, J) 9.9 Hz, H-6ax and H-4′), 3.67 (1H, dd, J2,3 ) 9.9 Hz, H-2),
3.64 (1H, t, J ) 9.3 Hz, H-4), 3.49 (3H, s, -OCH3), 3.40 (1H, bd,
J ) 10.2 Hz, H-6′a), 2.96 (1H, dd, J5,6b ) 4.2 Hz, H-6′b); 13C
NMR (CDCl3, 75 MHz) δ 143.9, 138.7, 138.6, 138.3, 137.9, 137.3,
128.8-125.9, 101.2, 97.2, 93.9, 86.1, 82.2, 79.5, 79.2, 78.1, 76.0,
2,3,4-Tri-O-benzyl-6-O-trityl-D-glucopyranosyl-(1 f 6)-1,2:
3,4-di-O-isopropylidene-R-D-galactopyranose (51): foam; 1H
NMR (CDCl3, 300 MHz) signals of the R anomer δ 7.60-6.80
(Ar), 5.56 (1H, d, J1,2 ) 4.8 Hz, H-1), 5.17 (1H, d, J1,2 ) 3.9 Hz,
H-1′), 5.00-4.30 (6H, 3 × AB, -CH2Ph), 4.64 (1H, dd, J2,3 ) 2.4
Hz, J3,4 ) 8.1 Hz, H-3), 4.41 (1H, dd, J4,5 ) 2.4 Hz, H-4), 4.35
(1H, dd, H-2), 4.10 (1H, dt, J5,6 ) 6.3 Hz, H-5), 4.00 (1H, t, J )
9.3 Hz, H-3′), 3.92-3.66 (4H, m, H-4′, H-5′, H2-6), 3.57 (1Η, dd,
J5,6a ) 2.1 Hz, J6a,6b ) 9.9 Hz, H-6a′), 3.23 (1Η, dd, J5,6b ) 4.2,
H-6b′), 1.54, 1.50, 1.35, 1.34 (12H, 4s, isopropylidene methyls);
13C NMR (CDCl3, 75 MHz) δ 143.9, 138.8, 138.5, 137.9, 128.7-
126.9, 109.2, 108.5, 96.3, 86.3, 82.1, 80.1, 77.9, 75.9, 72.9, 72.2,
70.7, 70.6, 70.4, 65.4, 62.4, 26.1 (×2), 24.9, 24.6; MS (MALDI-
TOF) calcd for (C58H62O11Na+) 957.41, found 957.5. Anal. Calcd
for C58H62O11: C, 74.50; H, 6.68. Found: C, 74.63; H, 6.73.
2,3,4-Tri-O-benzyl-6-O-dimethoxytrityl-D-glucopyranosyl-
(1 f 6)-1,2:3,4-di-O-isopropylidene-R-D-galactopyranose (52):
foam; 1H NMR (CDCl3, 300 MHz) signals of the R anomer δ 7.60-
6.70 (Ar), 5.53 (1H, d, J1,2 ) 4.8 Hz, H-1), 5.13 (1H, d, J1,2 ) 3.6
75.6, 74.8, 73.9, 72.9, 70.4, 69.0, 62.3, 62.1, 55.0; [R]25 +19.6
D
(c 1.0, CHCl3); MS (MALDI-TOF) calcd for (C67H66O11Na+)
1069.46, found 1069.5. Anal. Calcd for C67H66O11: C, 76.84; H,
6.35. Found: C, 76.61; H, 6.27.
Acknowledgment. We thank Dr. Emiliano Bedini for helpful
discussions. This research was financially supported in part by
MIUR (PRIN funds). NMR and MS facilities of CIMCF are
acknowledged.
Supporting Information Available: Copies of 1H and 13C NMR
spectra of compounds 9-27 and disaccharides 34-41, 44-48, and
51-53. This material is available free of charge via the Internet at
http://pubs.acs.org.
Hz, H-1′), 4.98-4.29 (6H, 3 × AB, -CH2Ph), 4.61 (1H, dd, J2,3
)
2.4 Hz, J3,4 ) 8.1 Hz, H-3), 4.38 (1H, dd, J4,5 ) 1.8 Hz, H-4),
JO070670O
6106 J. Org. Chem., Vol. 72, No. 16, 2007