Stereoselective synthesis of 2-deoxy-2-iodo-glycosides from furanoses. A new route to 2-deoxy-glycosides and 2-deoxy-oligosaccharides of ribo and xylo configuration

Article abstract of DOI:10.1021/jo051461b

A general procedure for the stereoselective synthesis of 2-deoxy-2-iodo-hexo- and -hepto-pyranosyl glycosides from furanoses is reported. The proposed methodology provides a new route for accessing 2-deoxy-oligosaccharides. The procedure involves three re

Full text of DOI:10.1021/jo051461b

Stereoselective Synthesis of 2-Deoxy-2-iodo-glycosides from
Furanoses. A New Route to 2-Deoxy-glycosides and
2-Deoxy-oligosaccharides of ribo and xylo Configuration
Miguel AÄ ngel Rodr´ıguez, Omar Boutureira, Xavier Arne´s, M. Isabel Matheu,
Yolanda D´ıaz,* and Sergio Castillo´n*
Departament de Quı´mica Analı´tica i Quı´mica Orga`nica, Universitat Rovira i Virigili,
C/ Marcel‚lı´ Domingo s/n, 43007 Tarragona, Spain
yolanda.diaz@urv.net; sergio.castillon@urv.net
Received July 14, 2005
A general procedure for the stereoselective synthesis of 2-deoxy-2-iodo-hexo- and -hepto-pyranosyl
glycosides from furanoses is reported. The proposed methodology provides a new route for accessing
2-deoxy-oligosaccharides. The procedure involves three reactions: Wittig-Horner olefination to
give alkenyl sulfanyl derivatives, electrophilic iodine-induced cyclization to give phenyl 2-deoxy-
2-iodo-1-thio-hexo-glycosides, and glycosylation. Protected furanoses 1, 3, and 6-11, which include
examples of the four possible isomeric configurations of furanoses, were reacted with diphenyl
phenylsulfanylmethyl phosphine oxide to give the alkenyl sulfanyl derivatives 2, 4, and 12-16.
The iodine-induced cyclization of these compounds afforded the phenyl 2-deoxy-2-iodo-1-thio-
glycosides 18, 20, and 22-27 with practically complete regio- and stereoselectivity. Products of
6-endo cyclization, in which the iodine at C-2 was in a cis relationship with the alkoxy at C-3, were
almost exclusively produced. Better yields were obtained for compounds with a ribo or xylo
configuration than for compounds with other configurations. Compounds 18, 20, and 22-27 were
found to be efficient glycosyl donors in the glycosylation of cholesterol and glucopyranoside 29a,
affording the corresponding 2-deoxy-2-iodo-glycosides and 2-deoxy-2-iodo-oligosaccharides with good
yields and stereoselectivities. The glycosydic bond in the major isomers was always trans to the
iodine at C-2.
Introduction
ride units belonging to the D and L series with all possible
configurations (Figure 1).
The 2-deoxy- and 2,6-dideoxyglycoside structural
motifs are present in many natural products with inter-
esting biological properties, including the aureolic acid
antibiotics (olivomycins, mithromycins, chromomycins),
the anthracycline antibiotics (cyclamycin 0), the angucy-
cline group of antibiotics (landomycin A), the enediynes
The stereocontrolled formation of the glycosidic link-
age in 2-deoxy-oligosaccharides has proved to be one of
the most challenging tasks in glycosylation reactions2
because of the absence of a stereodirecting group at
C-2. This problem can be overcome by using electron-
donating groups (such as iodo, phenylsulfanyl, and
phenylselenenyl) as stereodirecting groups at position 2
of the glycosyl donor in the glycosylation step. Once
I
(calicheamycin γ1 , esperamycins A1 and C), cardiac
glycosides (digitoxine), and antiparasital agents (aver-
mectins). Removing deoxysugars from these clinically
important molecules often severely decreases their ef-
ficiency and/or specificity. Deoxysugars also play an
important role in lipopolysaccharides, glycoproteins, and
glycolipids, where they act as ligands for cell-cell
interactions or as targets for toxins, antibodies, and
microorganisms.1 These compounds contain monosaccha-
(1) (a) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99. (b)
Albrecht, H. P. Cardiac Glycosides. In Naturally Ocurring Glycosides;
Ikan, R., Ed.; Wiley: Chichester, UK, 1999. (c) Glycoconjugates:
Composition, Structure and Function; Allen, H. J., Kisailus, E. C., Eds.;
Marcel Dekker: New York, 1992.
(2) (a) Kirschning, A.; Jesberger, M.; Scho¨ning, K.-U. Synthesis 2001,
507. (b) Veyrie`res, A. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley: Weinheim, 2000; Part
I, Vol. I, p 367. (c) Marzabadi, H.; Franck, R. W. Tetrahedron 2000,
56, 8385. (d) Castro-Palomino, J. C.; Schmidt, R. R. Synlett 1998, 501.
(e) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
* To whom correspondence should be addressed. Fax: 34-977-
558446.
10.1021/jo051461b CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/05/2005
J. Org. Chem. 2005, 70, 10297-10310
10297

Rodr´ıguez et al.
SCHEME 2
olivose) and 2-deoxy-L-fuco-pyranosides. However, there
are only a few reported examples of the synthesis of 2,6-
dideoxy-D-ribo-hexo-glycosides (D-digitoxose),7 and no
examples of the synthesis of 2,6-dideoxy-D-xylo-hexo-
glycosides (D-boivinose), probably because of the difficulty
of obtaining the corresponding glycals.
FIGURE 1. Examples of 2-deoxyoligosaccharide molecules
containing configurationally different 2-deoxysugars.
2-Deoxy-phosphites,8 -phosphoroimidates,9 and -dithio-
phosphates10 have also been used as glycosyl donors to
provide mainly the R derivative.
SCHEME 1
Here we report a procedure for synthesizing phenyl
2-deoxy-2-iodo-1-thio-glycosides11,12 and the use of these
glycosides as glycosyl donors for the stereocontrolled
synthesis of 2-deoxy-2-iodo-disaccharides. The key step
in the proposed synthesis of 2-deoxy-2-iodo-1-thio-glyco-
sides is a cyclization of alkenols induced by iodine-
containing electrophiles. These alkenols can be prepared
by an olefination reaction starting from protected fura-
noses (Scheme 2). This procedure is particularly efficient
for the synthesis of 2-deoxy-â-hexo-glycosides of ribo or
xylo configuration.13
obtained, the 2-heteroatomic-substituted glycosides can
be further reduced to provide the corresponding 2-deoxy-
glycosides.
Glycosylation can be performed from glycals by activa-
tion with iodine,3 sulfanyl,4 or selenenyl5 electrophiles
through a one-pot procedure to afford mainly trans-
diaxial (I+) or trans-diequatorial (S+, Se+) addition prod-
ucts (Scheme 1a). Glycosylation can also be performed
in a two-step procedure by first isolating a 2-deoxy-2-X-
glycosyl donor (X ) I, SR, SeR) and then activating it in
the presence of a glycosyl acceptor.6 2-Deoxyglycosides
can also be directly synthesized by acid-catalyzed addi-
tion of an alcohol to a glycal, as exemplified in the
synthesis of digitoxine, where the starting 6-deoxy-allal
is prepared from a non-carbohydrate precursor (Scheme
1b).7
Results and Discussion
The first step in the proposed synthesis of 2-deoxy-2-
iodo-1-thio-glycosides was olefination of a series of prop-
erly protected furanoses to afford the corresponding
enolthioethers. The hydroxyl groups in furanoses 1, 3,
6, 8, and 11 were protected as benzyl ethers, although
acetonides (7, 9, and 10) and silyl ethers (9) were also
used as protecting groups. The reaction conditions for
olefination were optimized by starting from ribose de-
rivative 1 and using different olefinating reagents, such
as ylides,14 phosphine oxides,15 phosphonates,14c and
silylcarbanions.16 Aucagne et al. recently used a Wittig
Most of these procedures have been applied to the
synthesis of 2,6-dideoxy-D-arabino-hexo-pyranosides (D-
(8) Hashimoto, S. I.; Sano, A.; Sakamoto, H.; Nakajima, I.; Yanagiya,
Y.; Ikegami, S. Synlett 1995, 1271.
(3) (a) Lemieux, R. U.; Levine, S. Can. J. Chem. 1964, 42, 1473. (b)
Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190. (c) Thiem,
J.; Karl H.; Schwentner, J. Synthesis 1978, 696. (d) Thiem, J.; Klaffke,
W. Top. Curr. Chem. 1990, 154, 285. (e) Danishesky, S.; Bilodeau, M.
T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380.
(4) (a) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 4701. (b)
Ramesh, S.; Franck, S. W. J. Chem. Soc., Chem. Commun. 1989, 960.
(c) Preuss, R.; Schmidt, R. R. Synthesis 1988, 694. (d) Grewal, G.; Kaila,
N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084.
(9) Li, H.; Chan, M.; Zhao, K. Tetrahedron Lett. 1997, 38, 6143.
(10) Bielawska, H.; Michalska, M. Tetrahedron Lett. 1998, 39, 9761.
(11) Thio-glycosides are useful glycosyl donors; see, for instance: (a)
Oscarson, S. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay¨, P., Eds.; Wiley: Weinheim 2000,; Part I, Vol. I, p
93. (b) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 172.
(12) Deoxy-thioglycosides have recently been used as glycosyl donors
in a solid-phase-assisted synthesis of 2-deoxyconjugates; see: Jaumzens,
J.; Hofer, E.; Jesberger, M.; Sourkouni-Argirusi, G.; Kirschning, A.
Angew. Chem., Int. Ed. 2003, 42, 1166.
(5) Perez, M.; Beau, J. M. Tetrahedron Lett. 1989, 30, 75.
(6) (a) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5, 1871. (b)
Chong, P. Y.; Roush, W. R. Org. Lett. 2002, 4, 4523. (c) Kirschning, A.;
Jesberger, M.; Scho¨ning, K.-U. Org. Lett 2001, 53, 3623. (d) McDonald,
F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000, 122, 4304. (e)
Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891. (f)
Roush, W. R.; Narayan, S.; Bennett, C. E.; Briner, K. Org. Lett. 1999,
1, 895. (g) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899. (h) Roush,
W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541. (i) Kirschning,
A. Eur. J. Org. Chem. 1998, 63, 2267. (j) Roush, W. R.; Sebesta, D. P.;
James, R. A. Tetrahedron 1997, 53, 8837. (k) Roush, W. R.; Sebesta,
D. P.; Bennett, C. E. Tetrahedron 1997, 53, 8825.
(13) For a preliminary communication, see: Arne´s, X.; D´ıaz, Y.;
Castillo´n, S. Synlett 2003, 2143.
(14) (a) Wittig, G.; Schlosser, M.; Chem Ber. 1961, 94, 1373. (b)
Vlatas, I.; Lee, A. O. Tetrahedron Lett. 1974, 4451; Bestmann, H. J.;
Angerer, J. Liebigs Ann. Chem. 1974, 2085.
(15) (a) (review) Clayden, J.; Warren, S. Angew. Chem., Int. Ed. Eng.
1996, 35, 241. (b) (SR, two-step) Earnshaw, C. E.; Wallis, C. J.; Waren,
S. J. Chem. Soc., Perkin Trans. 1 1979, 3099. (c) (SR, one-step)
Grayson, J. I.; Warren, S. J. Chem. Soc., Perkins Trans. 1 1977, 2263.
(16) (a) (review) van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem.
Soc. Rev. 2002, 31, 195. (b) Ager, D. J. J. Chem. Soc., Perkins Trans.
1 1986, 183.
(7) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40,
3653.
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Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
TABLE 1. Optimization of Olefination Conditions of
Furanose 1 To Obtain Thioalkene 2a
TABLE 2. Optimization of the Olefination Conditions of
Furanose 3a
yield (%)
entry
X
temp (°C)
(Z/E ratio)b
1
2
3
4
5
PPh3
0 f rt
-78 f rt
-78 f rt
-78 f reflux
-78 f rt
(Et2O)PO
Ph2PO
Ph2PO
Me3Si
18 (0:1)
35 (1:4)
72 (1:4)
50 (3:2)
yield (%)
a Base ) BuLi, solvent ) THF. b Determined by integration of
the olefinic proton signals in the 1H NMR spectrum of the crude
reaction mixture.
entry
X
temp (°C)
product
(Z/E ratio)b
1
2
3
4
5
PPh3
0 f rt
-78 f rt
rt
-78 f rt
-78 f rt
4
4
4
4
4
70 (1:4)
23 (0:1)
85 (1:3)
100 (2:3)
61 (3:2)
(Et2O)POc
Ph2PO
Ph2PO
Me3Si
reaction to synthesize carbohydrate-derived vinyl sulfides
in good yields with, in general, preferential formation of
the Z isomer.17 Reaction of 1 under Wittig conditions fur-
nished a complex mixture (Table 1, entry 1). Wadsworth-
Emmons olefination led to the formation of the desired
alkene 2 in low yield regardless of the base used but with
complete E-stereoselectivity (Table 1, entry 2). Peterson
olefination with silyl carbanions afforded enolthioether
2 in 50% yield as a Z/E mixture, but small amounts of a
secondary product, formed by epimerization at the allylic
position, were isolated (Table 1, entry 5).18 To prevent
epimerization, cerium-modified Peterson olefination19
was carried out, but only the starting material was
recovered. The highest yields of alkene 2 (72%) were
obtained when a phosphine oxide was used and n-BuLi
was used as the base (Table 1, entries 3, 4). As expected
for a semistabilized olefinating reagent, the stereoselec-
tivity was low and an inseparable 1:4 Z/E mixture was
obtained.
a Base ) BuLi, solvent ) THF. b Determined by integration of
the olefinic proton signals in the 1H NMR spectrum of the crude
reaction mixture. c Base ) LDA. c 10% of compound 5 was also
obtained.
TABLE 3. Olefination of Furanoses 6-11a
To determine the generality of the reaction and the
influence of the stereochemistry at position 2, arabinose
derivative 3 was also subjected to a range of olefination
conditions. The behavior observed was similar to that
found for furanose 1. Wittig olefination afforded the
alkene 4 in a 70% yield, together with a 10% of diene 5
as a result of a tandem olefination-elimination process
(Table 2, entry 1).17 As already observed for 1, reaction
of 3 with phosphonates afforded alkene 4 in modest yields
with complete stereoselectivity (Table 2, entry 2). Peter-
son olefination of 3 yielded 4 in moderate yield (61%) as
a Z/E mixture (Table 2, entry 5). The Wittig-Horner
reaction with the corresponding phosphine oxide was the
best choice; it afforded alkene 4 quantitatively as a 2:3
Z/E mixture (Table 2, entries 3 and 4).
The Wittig-Horner reaction with Li-bases is ideally
described as a two-step procedure in which a â-hydroxy-
phosphine oxide intermediate is formed and then sub-
sequently transformed to the alkene by reaction with KH
or NaH.20 With semistabilized reagents, however, the
alkene can be obtained directly.15c
a Reaction conditions: ratio substrate/phosphine oxide/BuLi )
1:4:4.4, solvent ) THF, temperature -78 °C to rt. b Determined
by integration of the olefinic proton signals in the 1H NMR
spectrum of the crude reaction mixture. c Additional yield obtained
by elimination of the isolated â-hydroxyphosphine intermediate.
d [Si]: tert-butyldiphenylsilyl.
(17) Aucagne, V.; Tatiboue¨t, A.; Rollin, P. Tetrahedron 2004, 60,
1817.
(18) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1986, 154, 270.
(19) Jonhson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281.
(20) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,
2307.
Once the optimal conditions had been established,
furanoses 6-11 were olefinated. The yield of benzylated
furanoses ranged from 60% (Table 3, entries 1 and 3) to
100% (entry 6). Isopropylidene-protected furanoses gave
J. Org. Chem, Vol. 70, No. 25, 2005 10299

Rodr´ıguez et al.
TABLE 4. Cyclization of Alkenyl Sulfide 2 Induced by Electrophilic Iodine Containing Reagents
entry
2 (Z/E ratio)a
[I] (equiv)
base (equiv)
solvent
temp (°C)
t (h)
product
yield (%)
a/â ratiob
1
0:1
1:2
1:2
2:3
1:2
I2 (3)
KH (1.3)
ether
-78 f rt
-78 f rt
-30 f rt
-78 f rt
-30
1
18
63
9
0:1
0:1
1:9
2
I2 (3)
KH (1.3)
ether
16
18
3
NIS (1.5)
NIS (1.5)
NIS (1.5)
NaHCO3 (1.5)
CH3CN
CH2Cl2
CH2Cl2
15
12
0.75
18
mixture
19
77
4
5c
64
1:41
a Determined by integration of the olefinic proton signals in the 1H NMR spectrum of the crude reaction mixture. b Determined by
1
integration of the anomeric proton signals in the H NMR spectrum of the crude reaction mixture. c Molecular sieves were added to the
reaction mixture.
TABLE 5. Cyclization of Alkenyl Sulfide 4 Induced by Electrophilic Iodine Containing Reagents
entry
4 Z/E ratioa
[I] (equiv)
base (equiv)
solvent
temp (°C)
t (h)
product
yield (%)
1
2
3
4
5
6
0:1
1:3
3:2
1:3
1:3
1:3
I2 (3)
KH (1.3)
ether
-78
1
1.5
16
3
18
18
20
21
20
20
20
20b
61
31
18
20
24
36
I2 (3)
KH (2.5)
ether
-78 f rt
I2 (3)
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (1.5)
CH3CN
CH3CN
CH3CN
CH3CN
-30 f rt
NIS (3)
NIS (3)
NIS (1.5)
-30
0
0
1
a Determined by integration of the olefinic proton signals in the H NMR spectrum of the crude reaction mixture. b Trace amounts of
the succinimido glycoside were detected by TLC.
lower yields (21-63%), probably due to higher steric
hindrance (Table 3, entries 2, 4, and 5). In contrast,
olefination of the 2-deoxy-ribose derivative 11 yielded
alkene 17 quantitatively. Starting from the lyxose and
erythrose derivatives 8, 9, and 10, the corresponding
â-hydroxyphosphine oxide intermediate was recovered
together with the alkene,14b so the former was subse-
quently treated with NaH. This increased the initial
alkene yields (52%, 21%, and 35%, respectively) to 62%,
31%, and 68%, respectively (Table 3, entries 3, 4, and 5).
In all cases, the Z/E mixtures of alkenes proved to be
inseparable; hence, the cyclization reactions were assayed
directly on the mixture of diastereomers. Cyclization from
the pure E alkenes was possible from the Wadsworth-
Emmons alkene products.
Electrophile-induced cyclization was first studied for
derivative 2. The reaction of diastereoisomerically pure
2E with iodine as the electrophile and KH as the base
afforded 2-deoxy-2-iodo-â-D-allo-thioglycoside 18 in 63%
yield (Table 4, entry 1). In contrast, when the reaction
was carried out starting from a 1:2 Z/E mixture under
the same conditions, 18â was obtained with the dra-
matically decreased yield of 9% (Table 4, entry 2).
Cyclization was also assayed using other electrophilic
reagents such as N-iodosuccinimide (NIS) with NaHCO3
as the base, and the best yields of thioglycoside 18 were
obtained after 15 h (77%, R/â ) 1:9) (Table 4, entry 3).
Under these conditions, traces of the succinimido glyco-
side 19 were detected by 1H NMR spectroscopy; this
glycoside was presumably formed by activation of the
anomeric phenylsulfanyl group in 18 and nucleophilic
attack of the succinimido anion. To diminish the nucleo-
philicity of the succinimido group when NIS was used
as the electrophilic reagent, the reaction was carried out
in the absence of base. Under these conditions, either a
complex mixture was obtained (Table 4, entry 4) or, when
molecular sieves were added to the reaction mixture, 19
was exclusively recovered in 64% yield as a 1:41 R/â
mixture (Table 4, entry 5).
The arabinose derivative 4 was then tested in the
cyclization reaction. Reaction of diastereomerically pure
4E with iodine and KH in ether afforded 2-deoxy-2-iodo-
R-manno-thioglycoside 20 exclusively in 61% yield (Table
5, entry 1). As for the ribose derivative 2, cyclization of
the Z/E mixture of 4 under the same conditions proved
difficult. Forcing the reaction conditions (higher temper-
atures and KH concentration) did not yield the desired
compound; rather it led to the formation of oxetane 21
in 31% yield as a result of isomerization of the double
bond to an enol ether and subsequent cyclization (Table
5, entry 2). Although the mechanism by which 21 was
formed was not studied in detail, deuteration experi-
ments seemed to exclude base-promoted isomerization of
the double bond. Isomerization may, however, have
occurred through a radical mechanism. Using a weaker
base such as NaHCO3 in combination with iodine led to
the formation of R-thioglycoside 20, but only in 18% yield
(Table 5, entry 3).
To increase the yield of the cyclization, the reaction
was also studied using NIS as the electrophile under
10300 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
TABLE 6. Cyclization of Alkenyl Sulfides 12-17
various conditions. The best results (36% yield of 20R)
were obtained using 1.5 equiv of NIS and 1.5 equiv of
NaHCO3 at 0 °C in CH3CN (Table 5, entry 6). The use of
NIS as the electrophile always led to the formation of
traces of the succinimido glycoside, similar to the behav-
ior of 2 described above. The Z isomer of 4 did not cyclize
under any of the conditions tested.
Induced by Electrophilic Iodine-Containing Reagents
These preliminary cyclization assays revealed that the
cyclization conditions are very sensitive to the configu-
ration of the hexenyl sulfide. The optimal conditions for
ribose derivative 2 are different from those for arabinose
4, which proved to be very resistant to cyclization. The
geometrical configuration of the alkene is also crucial for
cyclization. The E isomer of the alkenes readily reacted
to give the corresponding thioglycosides in moderate to
good yield, whereas the Z isomers either required a
higher temperature to cyclize or did not cyclize. This
difference in reactivity between the Z and E alkenes
makes it necessary to force the conditions to ensure full
conversion when starting from inseparable Z/E mixtures
of alkenes, which leads to partial decomposition of the
thioglycoside products. This decomposition process is the
cause of the low thioglycoside yields obtained from the
cyclization reactions of the arabino derivative 4 and, to
a lesser extent, the ribo derivative 2 (Table 4). In light
of the results obtained, the cyclization conditions for
compounds 12-17 had to be optimized. Table 6 sum-
marizes the reaction conditions that gave the best result
for each substrate. For the cyclization of 12, the best
conditions were to use iodonium dicollidine perchlorate
(IDCP) as the electrophilic reagent in CH3CN, which
afforded 2-deoxy-2-iodo-guloside 22 (77%) as a 1:10 R/â
mixture (Table 6, entry 1). As shown by the R/â ratio,
the Z isomer undergoes cyclization, although it requires
higher temperatures (∆T ∼10 °C) than the E isomer. The
same conditions were found to be the optimal for the
cyclization of 13 into 2-deoxy-2-iodo-D-glycero-talo-
pyranoside 23.
From diastereomerically pure 13E, 23R was exclusively
obtained in 97% yield (Table 6, entry 2). In contrast,
cyclization of a 1:6 Z/E mixture of 13 rendered 23R but
in a much lower yield (48%) (Table 6, entry 3). Forcing
the reaction conditions (higher temperatures and longer
reaction times) led to cyclization of both the E and Z
isomers to give 23 in 60% yield (R/â ratio ) 2:1) but also
produced the corresponding 2-iodo-lactol (16%) as a
consequence of the activation of the sulfanyl group in the
product 23.
a Determined by integration of the olefinic protons signals in
the 1H NMR spectrum of the crude reaction mixture. b Determined
by integration of the anomeric protons signals in the 1H NMR
spectrum of the crude reaction mixture. c 60% of 23 (2:1 R/â ratio)
and the corresponding 2-iodo-lactol (16%) were obtained when the
reaction mixture was stirred at room temperature for a prolonged
time. d Conversion: 69%. e 33% of the corresponding 2-iodo-lactol
was also obained. f A 1:1 C-2 epimeric mixture was obtained, which
decomposed on standing.
Reaction of the lyxo derivative 14 with IDCP in CH2Cl2
afforded 2-iodo-R-talo-pyranoside 24 in 20% yield
together with 2-iodo-â-galacto-pyranoside 25 in 15%
yield.
Slightly better results were obtained in the reaction
of the isopropylidene-protected lyxo derivative 15 with
NIS in acetonitrile, which gave the 2-iodo-talo-pyranoside
26 in 55% yield as a 42:1 R/â mixture.
The effect of the substitution of the hydroxyl-bearing
carbon atom on the cyclization was also studied. Treat-
ment of the erythrose derivative 16 with IDCP in
propionitrile at -78 °C gave the 2-iodo-thioglycoside 27
in 33% yield, together with the corresponding 2-iodolactol
in the same yield.
sulfide 17, which lacks an allylic alkoxy group. The
reaction of 17 with NIS afforded a mixture of four
compounds that were separated into two fractions. On
the basis of NMR spectroscopic analysis, these fractions
were assigned to a 1:1 C-2 epimeric mixture of 2,3-
dideoxy-2-iodo-thioglycosides with their corresponding
R/â anomers (47% yield, Table 6, entry 7).
This series of experiments established that the
hydroxy-hexenyl sulfides 2, 4, and 12-17 undergo a
completely 6-endo regioselective electrophilic iodine
reagent-induced cyclization. The normal 5-exo course
observed in analogue hexenols is biased to the 6-endo
mode by the presence of an electron-donating atom at
the terminus of the double bond. Sulfur stabilizes a
positive charge on the neighboring carbon atom, making
the 6-endo cyclization possible.
To gain insight into the stereochemical outcome, the
cyclization was carried out starting from the alkenyl
J. Org. Chem, Vol. 70, No. 25, 2005 10301

Rodr´ıguez et al.
SCHEME 3. Proposed Models for the
Electrophile-Induced Cyclization Reactions of
E-Hydroxy-alkenyl Sulfides 2, 4, and 12-17
SCHEME 4. Proposed Models for the
Electrophile-Induced Cyclization of
Z-Hydroxy-alkenylsulfides 2, 4, and 12-17
Furthermore, the cyclization reaction is highly stereo-
selective and very predictable in terms of the stereo-
chemical outcome. The relative stereochemistry of C-1
and C-2 in thioglycosides depends on the configuration
of the starting alkene. Thus, the reaction of the E-alkenyl
sulfide yields a cyclization product in which the iodine
atom and phenylsulfanyl group are in a trans arrange-
ment. In all cases where the Z alkene underwent cycliza-
tion, 2-iodo-thioglycosides were obtained with the sub-
stituents at C-1 and C-2 in a cis disposition.
tion in the cyclization of 17, the cyclization reaction yields
a C-2 epimeric mixture of 2-iodo-thioglycosides.
Another important issue associated with stereoselec-
tivity is the formation of cyclized products in which the
iodo group at C-2 is always cis with respect to the alkoxy
group at C-3. This is a key point in the global process
because the iodine configuration determines the config-
uration of the anomeric center in the glycosylated prod-
ucts. The stereoselectivity observed for the alkenes
considered here is consistent with that reported for
alkenols with an allylic alkoxy group21 and is determined
by a stereoelectronic effect known as the “inside-alkoxy
effect”.22 This effect favors cyclization from the most
reactive conformation, in which the allylic alkoxy group
is placed inside the plane that configures the framework
of the double bond. In this conformation, the σ* C-O
orbital is perpendicular to the π-system of the double
bond, which minimizes the electron-withdrawing effect,
causing the double bond to be more electron-rich and
hence more reactive toward electrophiles.
The inside-alkoxy effect may well explain why the Z
thioether is less reactive than the corresponding E isomer
(Schemes 3 and 4). Specifically, the inside-alkoxy con-
formation of the Z alkenes is sterically crowded and,
therefore, the activation energy that must be overcome
to form the transition state in the cyclization will be
higher than for the corresponding E alkenes. For some
compounds, such as the arabinose derivative, the activa-
tion energy is sufficiently high that cyclization is pre-
cluded. Although such compounds could also undergo
cyclization via the outside-alkoxy conformation, this
conformation is insufficiently reactive to promote cycliza-
tion.
An exception to the inside-alkoxy effect rule is the lyxo
derivative 14, which undergoes cyclization to give a
mixture of the expected pyranoside 24 together with 25,
where the latter product is formed by cyclization of the
E isomer of 14 through a transition state in which the
alkoxy group is located in an outside position. The
formation of outside-alkoxy products has previously been
described in relation to electrophile-induced cyclizations
of Z-enolethers to give cyclohexyl pyranosides.23 These
previous results, however, can be accounted for in terms
The stereodirecting role of the allylic group is evident
in the cyclization of 17, which lacks an allylic OR group.
Since there is no stereoelectronically preferred conforma-
(21) (a) Landais, Y.; Panchenault, D. Synlett 1995, 1191. (b) Bravo,
F.; Castillo´n, S. Eur. J. Org. Chem. 2001, 507.
(22) (a) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, 3951. (b)
Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Ja¨ger, V.; Schohe,
R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880. (c) Halter, J.;
Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 8031.
(23) (a) Suzuki, K.; Mukaiyama, T. Chem. Lett. 1982, 683-686. (b)
Suzuki, K.; Mukaiyama, T. Chem. Lett. 1982, 1525.
10302 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
TABLE 7. Stereoselective Glycosylation of 29a and 29b
of the high steric hindrance of the inside-alkoxy confor-
mation in the Z alkenes and the presence of an electron-
rich double bond, which will be reactive toward cycliza-
tion even in the outside-alkoxy conformation. In contrast,
cyclization of 14E is not subject to 1,3-allylic strain and
therefore the inside-alkoxy conformation should be the
lowest-energy conformation. In fact, aside from 14, none
of the other alkenes studied, including the isopropylidene
lyxo derivative 15, gave outside-alkoxy products. At
present we do not have an explanation for the formation
of 25.
from 2-Deoxy-2-iodo-thioglycosides 18, 20, 22, 23, 26, and
27
The inside-alkoxy effect can also explain why the
reactivities of the ribo and xylo derivatives differed from
those of the arabino and lyxo derivatives (Scheme 3). For
the ribo and xylo derivatives 2 and 12, the most stable
conformer is the one that leads to the preferred transition
state for cyclization, that is, the conformation in which
the large alkyl group is anti to the incoming electrophile
and the allylic alkoxy group occupies the inside position.
As a result, the cyclization readily proceeds. For the
arabino and lyxo derivatives 4 and 14, by contrast, the
preferred conformation (outside-alkoxy) is not the one
that favors cyclization, and hence a conformational
change must occur for cyclization to proceed. For these
molecules, the preferred transition state has a boatlike
conformation, which is higher in energy than the transi-
tion states of the ribo and xylo derivatives. Consequently,
the cyclization is slower for the arabino and lyxo deriva-
tives than for the ribo and xylo derivatives.
The higher reactivity of 13 compared to 4 can be
explained by the presence of the isopropylidene group,
which restricts the conformational freedom and accord-
ingly favors cyclization. The cyclization yield of thio-
alkenes with arabino and lyxo configurations is low
because the initially produced thioglycoside is further
activated under the cyclization conditions because the
electrophilic reagent used for the cyclization, NIS, can
also activate the thioglycoside.
Cyclization of the erythro derivative 16 to produce 27
should be easy, as for the ribo and xylo derivatives 2 and
12. The low yield (33%) of 27 is a consequence of its high
reactivity toward the activation of an anomeric phenyl-
sulfanyl group in the presence of IDCP even at -78 °C.
This reactivity is general to all 6-deoxy-glycosides.24
Under these conditions, the initially formed 2-iodo-
thioglycoside 27 was partially consumed to produce the
corresponding 2-iodo-lactol in 33% yield. In this context,
the R/â ratio of 27 may not reflect the diastereoselectivity
of the cyclization, because the two thioglycoside anomers
may be activated at different rates.
a 1 mmol glycosyl donor, 2 mmol glycosyl acceptor, dry CH2Cl2,
NIS (2.2 mmol), 20 mol % TfOH. b Determined by integration of
the anomeric proton signals in the 1H NMR spectrum of the crude
reaction mixture.
The 2-deoxy-2-iodo-thioglycosides 18, 20, 22, 23, 24,
26, and 27 were found to be quite stable and can be stored
in the refrigerator for several months without significant
decomposition. The only labile 2-deoxy-2-iodo-thioglyco-
sides were 25 and 28, which decomposed on standing.
The glycosyl donors 18, 20, 22, 23, 26, and 27 were
tested for stereoselective glycosylation of methyl 4,6-O-
benzylidene-3-O-benzyl-R-D-glucoside (29a) and choles-
terol (29b) under typical conditions for thioglycosides25
(Table 7). Starting from 1,2-trans-diequatorial substi-
tuted glycosyl donors 18 and 22, glycosides 30 and 32
were obtained in yields of 61% to 81% with R/â ratios
between 1:6 and 1:16 (Table 7, entries 1 and 3). Treat-
ment of 20 with NIS/TfOH in the presence of 29a
afforded 2-deoxy-2-iodo-mannoside 31a as a 45:1 R/â
mixture in 71% yield. Glycosylation of 29b afforded 31b
with slightly lower stereoselectivity (R/â ratio ) 37:1) in
71% yield (Table 7, entry 2). Similar behavior was
observed in the glycosylation of 29a and 29b with 23 to
afford 33a and 33b in 69% and 57% yield, respectively,
although the glycosylation of 29b proceeded with lower
R-selectivity (8:1), probably due to the higher tempera-
ture required to promote glycosylation (Table 7, entry 4).
(24) See ref 6e and references therein.
(25) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331.
J. Org. Chem, Vol. 70, No. 25, 2005 10303

Rodr´ıguez et al.
SCHEME 5
When compared with 18 and 22, the 1,2-trans-diaxial
substituted glycosyl donors 20, 23 and 26 provided
improved stereoselectivities, especially in the glycosyl-
ation of 29a. These results are in agreement with those
reported by Roush and Narayan for the glycosylation
of 2-deoxy-2-iodo-manno- and 2-deoxy-2-talo-pyranosyl
acetates.6g
To address the stereoselectivity of glycosylation of the
gulo derivative 22, both the conformational preferences
and relative reactivities of the intermediate pyranosyl
oxocarbenium ions a and b implicated in this reaction
must be taken into account.26,6a
According to the work of Ayala et al.,26a the diaxial
oxocarbenium b is likely to be more stable than a,
suggesting that the attack of the alcohol would prefer-
entially give the R-derivative. However, for the nucleo-
phile to attack the lower energy diaxial conformer b, it
must overcome steric interactions with the pseudoaxial
C-3 benzyloxy substituent, which will attenuate the
reactivity of b. By contrast, the incoming nucleophile does
not need to overcome this steric interaction with the C-3
substituent when approaching the diequatorial conformer
a. Hence, although a is predicted to be higher in energy
than b, it is potentially more reactive. Consistent with
this, glycosylation of 22 affords the â-anomers 32a and
32b, indicating that the nucleophile attacks the diequa-
torial oxocarbenium ion conformer. This type of stereo-
chemical control is consistent with Curtin-Hammett
kinetics.
Glycosylation of 29a with the glycosyl donor 27 af-
forded 35a in 44% yield with moderate (1:3) â-selectivity.
As observed previously for 6-deoxy-glycosides,24 thio-
glycoside 27 was very reactive toward glycosylation and
required very low temperatures (-78 °C). Because gly-
cosylation of cholesterol was difficult to monitor by TLC,
higher temperatures and a longer reaction time were
used to ensure maximum conversion to glycoside 35b,
which was obtained in 46% yield with selectivity R/â )
1:25 (Table 7, entry 6).
constrained by protecting groups such as isopropyl-
idene groups. The cyclization reaction proceeds with
complete regio- and stereoselectivity. The reaction pro-
ceeds exclusively as 6-endo cyclization to give phenyl
1-thio-pyranoside derivatives. The stereochemistry of the
iodine at C-2 is always cis to the neighboring alkoxy
group, except for 25. This is a key point in the overall
process because the iodine controls the stereoselectivity
of the glycosylation reaction. The yield of the cyclization
depends on the configuration of the starting material; it
is very good for substrates with a ribo or xylo configura-
tion but more modest for those with an arabino or lyxo
configuration. The glycosylation reaction carried out with
cholesterol, which can be looked upon as a model of the
aglycones present in natural products, and with mono-
saccharide 29a proceeded with good yields and good to
excellent stereoselectivities. The glycosidic bond created
in the major isomers was always trans to the iodine at
C-2.
Although phenyl 2-deoxy-2-iodo-1-thio-glycosyl donors
of all configurations can be accessed using the proposed
procedure, it is particularly effective at providing 2-deoxy-
2-iodo-D-gulo- and -D-allo-glycosides (Scheme 5). These
glycosides are precursors of 2-deoxy-glycosides of ribo and
xylo configuration, which are difficult to obtain by the
classical methodology starting from glycals.3e,27
Conclusion
Experimental Section
We have presented a general procedure for the stereo-
selective synthesis of 2-deoxy-2-iodo-hexo-pyranosyl gly-
cosides from furanoses. The proposed methodology pro-
vides a new avenue for accessing 2-deoxy-oligosaccharides.
The procedure involves three reactions: Wittig-Horner
olefination to give alkenyl sulfanyl derivatives; electro-
philic iodine-induced cyclization to give phenyl 2-deoxy-
2-iodo-1-thio-pyranosides, a new type of glycosyl donor;
and glycosylation. The olefination reaction affords the
alkenyl sulfanyl derivatives in good to excellent yields,
except in cases where the conformational freedom is
General Remarks. Optical rotations were measured at
room temperature in 10 cm cells. 1H, 13C, and 31P NMR spectra
were recorded using a 300 and 400 MHz apparatus, with
CDCl3 as solvent, Me4Si as an internal reference, and H3PO4
(31P) as external standard, unless specified otherwise. Elemen-
tal analyses were performed in the Servei de Recursos
Cient´ıfics (URV). Flash column chromatography was per-
formed using silica gel 60 A CC (230-400 mesh). Radial
chromatography was performed on 1, 2, or 4 mm plates of
Kieselgel 60 PF254 silica gel, depending on the amount of
product. Medium-pressure liquid chromatography (MPLC) was
performed using silica gel 60 A CC (6-35 µm). Solvents were
purified using standard procedures.
(26) (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521. (b) Bravo, F.; Viso,
A.; Alca´zar, E.; Molas, P.; Bo, C.; Castillo´n, S. J. Org. Chem. 2003, 68,
686.
(27) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org.
Chem. 1990, 55, 1979.
10304 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
Wittig-Horner Olefination of Furanoses 1, 3, and
6-11. To a solution of diphenyl phenylsulfanylmethyl phos-
phine oxide (4 mmol) in THF (26 mL) at -78 °C was added
BuLi (4.4 mmol). The mixture was left to stir at low temper-
ature for 30 min. A solution of the corresponding furanose (1
mmol) in THF (2 mL) was then added dropwise. The mixture
was allowed to warm to room temperature overnight. A
saturated solution of NH4Cl was then added and the olefina-
tion product was extracted with ether. The combination of
ethereal layers was dried with MgSO4 and concentrated. The
reaction crude was purified by chromatographic techniques.
Elimination from the â-Hydroxy-phosphine Oxide
Intermediate To Afford the Alkene. A mixture of the â-
hydroxyphosphine oxide intermediate and diphenyl (phenyl-
thiomethyl)phosphine oxide, recovered from the Wittig-
Horner reaction, was solved in THF (30 mL) and then the same
amount in weight of NaH 60% was added. The reaction
mixture was stirred at room temperature for 5 h and then
quenched by adding saturated aqueous NH4Cl. The mixture
was extracted with Et2O, dried over MgSO4, and concentrated
under reduced pressure. The crude was purified by chromato-
graphic techniques to afford the alkene.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-phenylsulfanyl-
D-ribo-hex-1-enitol (2). As described in the general proce-
dure, 1 (5.5 g, 13 mmol) was olefinated by reaction with
diphenyl (phenylthiomethyl)phosphine oxide (16.9 g, 52.2
mmol) and BuLi (35.9 mL of 1.6 M hexane solution, 57.4 mmol)
for 48 h under refluxing conditions. Column chromatography
(hexane to EtOac/hexane 1:3) afforded 2 (4.96 g, 72%) as an
inseparable 1:4 Z/E mixture as a yellowish syrup. Data
obtained from the mixture. Rf (EtOAc/hexane 1:3): 0.27. Anal.
Calcd for C33H34O4S: 75.25 C, 6.51 H, 6.09 S. Found: 75.27
C, 6.50 H, 6.12 S. 2E: 1H NMR (CDCl3, 400 MHz) δ 7.35-
7.22 (m, 20H), 6.50 (d, J ) 16, 1H), 5.91 (dd, J ) 16, 8, 1H),
4.77 (d, J ) 11.2, 1H), 4.67 (d, J ) 11.6, 1H), 4.56 (d, J ) 11.2,
1H), 4.51 (d, J ) 12, 1H), 4.48 (d, J ) 12, 1H), 4.40 (d, J )
11.6, 1H), 4.23 (dd, J ) 8.8, 4.4, 1H), 4.84-3.82 (m, 1H), 3.64-
3.58 (m, 2H), 3.70 (dd, J ) 7.6, 4, 1H), 2.72 (d, J ) 4.4, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 138.6-134.8, 130.2-126.9,
129.0, 128.7, 81.5, 81.0, 74.4, 73.6, 71.1, 71.0, 70.7. 2Z: 1H
NMR (CDCl3, 400 MHz) δ 7.35-7.22 (m, 20H), 6.58 (d, J )
9.6, 1H), 5.95 (dd, J ) 9.6, 9.6, 1H), 4.84-4.45 (m, 6H), 3.87-
3.85 (m, 1H), 3.77 (dd, J ) 8.4, 4, 1H), 3.68-3.65 (m, 1H),
3.64-3.58 (m, 2H), 2.78 (d, J ) 4.8, 1H). 13C NMR (CDCl3,
100.6 MHz) δ 138.6-134.8, 130.2-126.9, 81.2, 77.4, 74.3, 73.5,
71.2, 71.0, 70.7.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-phenylsulfanyl-
D-arabino-hex-1-enitol (4). According to the general proce-
dure above, the title compound was synthesized starting from
2,3,5-tri-O-benzyl-â-D-arabino-furanoside (3) (2 g, 4.76 mmol),
diphenyl (phenylthiomethyl)phosphine oxide (6.17 g, 19 mmol)
and BuLi (13 mL of 1.6 M hexane solution, 20.9 mmol).
Column chromatography (EtOac/hexane 1:3) afforded 4 (2.50
g, 100%) as an inseparable 1:3 Z/E mixture as a yellowish
syrup. Rf (EtOAc/hexane 1:3): 0.16. Data obtained from the
mixture. Anal. Calcd for C33H34O4S: 75.25 C, 6.51 H, 6.09 S.
Found: 74.97 C, 6.49 H, 6.07 S. 4E: 1H NMR (CDCl3, 400
MHz) δ 7.40-7.15 (m, 20H), 6.46 (d, J ) 15.2, 1H), 5.87 (dd,
J ) 15.2, 7.6, 1H), 4.65 (d, J ) 12.0, 1H), 4.57 (d, J ) 11.4,
1H), 4.52 (d, J ) 11.4, 1H), 4.49 (s, 2H), 4.38 (d, J ) 12.0,
1H), 4.16 (dd, J ) 8.0, 3.6, 1H), 4.00 (m, 1H), 3.58 (m, 3H),
2.76 (d, J ) 5.2, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 140.8,
137.7, 137.5, 134.0, 130.2-126.0, 80.4, 79.1, 74.1, 73.2, 70.7,
70.1, 69.9. 2Z: 1H NMR (CDCl3, 400 MHz) δ 7.35-7.25 (m,
20H), 6.52 (d, J ) 9.6, 1H), 5.96 (dd, J ) 9.6, 9.6, 1H), 4.71
(m, 1H), 4.68 (d, J ) 11.6, 1H), 4.67 (d, J ) 11.6, 1H), 4.57 (d,
J ) 11.2, 1H), 4.52 (d, J ) 11.6, 1H), 4.48 (d, J ) 11.6, 1H),
4.42 (d, J ) 11.6, 1H), 3.88 (m, 1H), 3.69 (dd, J ) 7.2, 4 Hz,
1H), 3.61 (m, 2H), 2.92 (d, J ) 5.2, 1H). 13C NMR (CDCl3, 100.6
MHz) δ 138.3-135.7, 129.6-127.1, 80.4, 75.9, 74.29, 73.6, 71.4,
71.3, 70.8.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-phenylsulfanyl-
D-xylo-hex-1-enitol (12). The title compound was prepared
following the general procedure above starting from 6 (1 g,
2.38 mmol) solved in THF (12 mL), diphenyl (phenylthio-
methyl)phosphine oxide (3.1 g, 9.54 mmol) in 10 mL of THF,
and n-BuLi (6.6 mL of 1.6 M hexane solution, 10.5 mmol) for
14 h. The reaction was monitored by TLC (EtOAc/hexane 1:3).
The crude was purified by column chromatography (EtOAc/
hexane 1:3) to afford 12 (60%) as an inseparable 1:4 Z:E
mixture as a yellowish syrup. 12E (obtained pure under
Wadsworth-Emmons conditions): [R]20D +6.48 (c 0.8 CHCl3).
1H NMR (CDCl3, 400 MHz) δ 7.27-7.15 (m, 20H), 6.42 (d, J
) 15.6, 1H), 5.68 (dd, J ) 15.6, 8.2, 1H), 4.75 (d, J ) 11.0,
1H), 4.57 (d, J ) 11.7, 1H), 4.46 (d, J ) 11.0, 1H), 4.34 (d, J )
11.0, 3H); 4.10 (dd, J ) 8.2, 7.5, 1H), 3.83 (m, J ) 6.0, 6.0,
2.6, 1H), 3.51 (dd, J ) 7.2, 2.6, 1H), 3.35 (m, J ) 6.0, 6.0, 5.7,
2H), 2.43 (s, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 138.2-127.2,
128.8, 128.0, 81.4, 80.2, 75.1, 73.3, 71.0, 70.8, 70.0. 0.37. Anal.
Calcd for C33H34O4S: 75.25 C, 6.51 H, 6.09 S. Found: 75.15
C, 6.53 H, 6.10 S. 12Z (spectroscopic data extracted from the
mixture): 1H NMR (CDCl3, 400 MHz) δ 7.38-7.24 (m, 20H),
6.55 (d, J ) 9.2, 1H), 5.82 (dd, J ) 9.6, 9.2, 1H), 4.88 (d, J )
11.2, 1H), 4.69 (d, J ) 12.0, 1H), 4.67 (dd, J ) 9.0, 3.0, 1H),
4.57 (d, J ) 11.2, 1H), 4.45 (d, J ) 12.0, 3H), 3.96 (m, J ) 6.8,
6.0, 2.8, 2.8, 1H), 3.72 (dd, J ) 6.0, 3.0, 1H), 3.43 (m, J ) 6.0,
2.8, 2.8, 2H), 2.53 (d, J ) 6.8, 1H). 13C NMR (CDCl3, 100.6
MHz) δ 138.4-127.1, 128.7, 128.0, 80.0, 77.3, 75.1, 73.4, 71.3,
71.1, 70.2.
(Z/E)-3,4:6,7-Di-O-isopropylidene-1,2-dideoxy-1-phenyl-
sulfanyl-D-manno-hep-1-enitol (13). Compound 7 (500 mg,
1.92 mmol) was olefinated according to the general procedure
by reaction with diphenyl (phenylthiomethyl)phosphine oxide
(2.49 g, 7.68 mmol) and n-BuLi (4.9 mL, 7.87 mmol). The
reaction was left to stir at room temperature for 21 h (TLC
control (EtOAc/hexane 1:3)). The crude was purified by column
chromatography (hexane to EtOAc/hexane 1:3) to afford 13
(447 mg, 63%) as a partially separable 1:4 Z:E mixture as a
colorless syrup. Rf (EtOAc/hexane 1:3): 0.28. 13E (obtained
pure under Wadsworth-Emmons conditions): [R]20 +23.10
D
1
(c 1.15 CH2Cl2). H NMR (CDCl3, 400 MHz) δ 7.40-7.25 (m,
5H), 6.56 (d, J ) 15.2, 1H), 6.03 (dd, J ) 15.2, 8.4, 1H), 4.78
(dd, J ) 8.4, 7.6, 1H), 4.36 (dd, J ) 7.6, 1.6, 1H), 4.09 (m, 1H),
4.01 (m, 2H), 3.45 (ddd, J ) 8.5, 8.4, 1.6, 1H) 2.21 (d, J ) 8.4
Hz, 1H), 1.51 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H).
13C NMR (CDCl3, 100.6 MHz) δ 134.4, 130.6, 129.3, 127.4,
130.4, 126.6, 109.5, 108.7, 78.6, 76.9, 76.2, 70.7, 67.2, 26.9, 26.8,
25.4, 24.6. Anal. Calcd for C19H26O5S: 62.27 C, 7.15 H, 8.75
S. Found: 62.06 C, 7.13 H, 8.73 S. 13Z (spectroscopic data
extracted from the mixture): 1H NMR (CDCl3, 400 MHz) δ
7.39-7.20 (m, 5H); 6.49 (d, J ) 9.6, 1H); 6.08 (dd, J ) 9.6,
7.6, 1H), 5.25 (dd, J ) 8.0, 5.7, 1H), 4.51 (d, J ) 8.0, 1H), 4.05
(m, 3H), 3.44 (m, 1H), 2.17 (d, J ) 8.8, 1H), 1.55 (s, 3H), 1.44
(s, 3H), 1.43 (s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3, 100.6 MHz)
δ 135.1, 130.7, 129.7, 129.4, 128.3, 128.2, 109.6, 109.0, 76.6,
76.3, 74.8, 70.6, 67.0, 27.1, 26.8, 25.5, 24.5.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-phenylsulfanyl-
D-lyxo-hex-1-enitol (14). As described in the general proce-
dure, the title compound was synthesized by reaction of 8 (386
mg, 0.92 mmol), diphenyl (phenylthiomethyl)phosphine oxide
(1.19 g, 3.67 mmol), and n-BuLi (2.5 mL of 1.6M hexane
solution, 4 mmol). Radial chromatography (from hexane to
EtOAc/hexane 1:1) furnished 14 (252 mg, 52%) as an insepa-
rable 1:17 Z/E mixture as a yellowish syrup and a low Rf
mixture of diphenyl (phenylthiomethyl)phosphine oxide and
the corresponding â-hydroxyphosphine oxide intermediate. The
mixture of phosphine oxides was submitted to elimination
conditions described above to afford an additional fraction of
14 (47 mg, 10%) as a 7:1 Z/E mixture. Data obtained from the
mixture. Rf (EtOAc/hexane 1:3): 0.22. Anal. Calcd for C33H34O4S:
75.25 C, 6.51 H, 6.09 S. Found: 75.23 C, 6.52 H, 6.06 S. 14E:
1H NMR (CDCl3, 400 MHz) δ 7.33-7.20 (m, 20H), 6.46 (d, J
) 15.2, 1H), 5.78 (dd, J ) 15.2, 8, 1H), 4.63 (d, J ) 11.2, 1H),
J. Org. Chem, Vol. 70, No. 25, 2005 10305

Rodr´ıguez et al.
4.62 (d, J ) 11.2, 1H), 4.49 (d, J ) 12.0, 1H), 4.45 (d, J ) 11.2,
1H), 4.44 (d, J ) 12.0, 1H), 4.38 (d, J ) 11.2, 1H), 4.13 (dd, J
) 7.0, 7.0, 1H), 4.06 (m, 1H), 3.57 (dd, J ) 7.0, 3.0, 1H), 3.50
(m, 2H), 2.71 (bs, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 138.1-
134.4, 130.3-127.2, 128.8, 128.5, 80.1, 79.8, 74.3, 73.4, 71.4,
70.8, 69.7. 14Z: 1H NMR (CDCl3, 400 MHz) δ 7.36-7.23
(m, 20H), 6.56 (d, J ) 9.2, 1H), 5.89 (dd, J ) 9.2, 9.2, 1H),
4.76 (d, J ) 12.0, 1H), 4.67 (m, 1H), 4.67 (d, J ) 11.6, 1H),
4.51 (d, J ) 11.6, 1H), 4.50 (d, J ) 12.0, 1H), 4.46 (d, J ) 12.0,
1H), 4.45 (d, J ) 12.0, 1H), 4.05 (m, 1H), 3.71 (dd, J ) 5, 3.4,
1H), 3.54 (m, 2H), 2.98 (bs, 1H). 13C NMR (CDCl3, 100.6 MHz)
δ 138.3-135.7, 129.6-127.0, 79.7, 76.4, 74.0, 73.5, 71.2, 71.1,
70.3.
(Z/E)-6-O-(tert-Butyldiphenylsilyl)-3,4-O-isopropylidene-
1,2-dideoxy-1-phenylsulfanyl-D-lyxo-hex-1-enitol (15). Ac-
cording to the general olefination procedure, compound 9
(723.9 mg, 1.69 mmol), diphenyl (phenylthiomethyl)phosphine
oxide (2.19 g, 6.76 mmol), and n-BuLi (4.6 mL of 1.6 M hexane
solution, 7.43 mmol) were left to react for 14 h. The reaction
was monitored by TLC (EtOAc/hexane 1:3). Column chroma-
tography (from hexane to EtOAc/hexane 1:3) afforded 15 (192
mg, 21%) as an inseparable 1:8 Z/E mixture as a yellowish
syrup and a low Rf mixture of diphenyl (phenylthiomethyl)-
phosphine oxide and the corresponding â-hydroxyphosphine
oxide intermediate that was submitted to the elimination
conditions described above to afford an additional fraction of
15 (80 mg, 10%) as a 1:1 Z/E mixture. 15E (obtained pure
under Wadsworth-Emmons conditions): Rf (EtOAc/hexane
1:3): 0.48. [R]20D +40.5 (c 1.00, CH2Cl2). 1H NMR (CDCl3, 400
MHz) δ 7.72-6.32 (m, 15H), 6.34 (d, J ) 15.2, 1H), 5.86 (dd,
J ) 15.2, 8.8, 1H), 4.55 (dd, J ) 8.0, 6.4, 1H), 4.29 (dd, J )
6.4, 3.6, 1H), 3.72-3.64 (m, 3H), 2.43 (d, J ) 6.0, 1H), 1.48 (s,
3H), 1.37 (s, 3H), 1.07 (s, 9H). 13C NMR (CDCl3, 100.6 MHz) δ
135.7-127.4, 130.0, 126.6, 108.8, 78.4, 77.4, 72.6, 70.1, 27.0,
26.7, 25.1, 19.4. Anal. Calcd for C33H34O4SSi: 69.62 C, 7.16
H, 6.00 S. Found: 69.66 C, 7.14 H, 6.04 S. 15Z (spectroscopic
data extracted from the mixture): 1H NMR (CDCl3, 400 MHz)
δ 6.39 (d, J ) 9.6, 1H), 5.99 (dd, J ) 9.6, 8.0, 1H), 5.15 (app.
t, J ) 8.0, 1H), 4.40 (dd, J ) 6.0, 3.0, 1H), 3.73-364 (m, 3H),
2,62 (bs, 1H), 1.52 (s, 3H), 1.42 (s, 3H), 1.1 (s, 9H). 13C NMR
(CDCl3, 100.6 MHz) δ 135.7-126.6, 114.2, 77.0, 74.5, 70.2, 65.2,
26.7, 27.2, 26.3, 19.1.
(Z/E)-3,4-O-Isopropylidene-1-phenylsulfanyl-D-erythro-
pent-1-enitol (16). The title compound was obtained from
2,3-O-isopropylidene-D-erythrose 10 (915.4 mg, 5.7 mmol),
diphenyl (phenylthiomethyl)phosphine oxide (7.4 g, 22.9 mmol),
and n-BuLi (15.7 mL of 1.6 M hexane solution, 25.1 mmol).
The reaction mixture was left to react for 16 h, monitored by
TLC (EtOAc/hexane 1:1). Column chromatography (from hex-
ane to EtOAc/hexane 1:1) rendered 16 (520 mg, 35%) as an
inseparable 1:3 Z/E mixture as a yellowish syrup and a low
Rf mixture of diphenyl (phenylthiomethyl)phosphine oxide and
the corresponding â-hydroxyphosphine oxide intermediate that
was submitted to the elimination conditions described above
to afford an additional fraction of 16 (500 mg, 33%) as a 12:1
Z/E mixture. Data obtained from the mixture: Rf (EtOAc/
hexane 1:1): 0.38. Anal. Calcd for C14H18O3S: 63.13 C, 6.81
H, 12.04 S. Found: 63.12 C, 6.81 H, 12.05 S. 16E: 1H NMR
(CDCl3, 400 MHz) δ 7.37-7.21 (m, 5H), 6.52 (d, J ) 15.0, 1H),
5.71 (dd, J ) 15.0, 8.0, 1H), 4.69 (t, J ) 6.4, 1H), 4.25 (m, 1H),
3.55 (m, 2H), 1.48 (s, 3H), 1.37 (s, 3H). 13C NMR (CDCl3, 100.6
MHz) δ 134.9, 130.5-126.8, 128.9, 125.5, 108.9, 78.5, 77.6,
61.9, 27.8, 25.2. 16Z: 1H NMR (CDCl3, 400 MHz) δ 7.41-7.22
(m, 5H), 6.45 (d, J ) 9.2, 1H), 5.86 (t, J ) 9.2, 1H), 5.15 (dd,
J ) 7.6, 7.6, 1H), 4.35 (m, 1H), 3.60 (m, 2H), 1.53 (s, 3H), 1.42
(s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ 135.0, 132.2-124.5,
128.4, 126.9, 109.1, 78.3, 74.3, 62.1, 27.8, 25.2.
hexane solution, 1.30 mmol) for 4 h. The reaction was
monitored by TLC (EtOAc/hexane 1:3). Column chromatogra-
phy (EtOAc/hexane 1:3) furnished 17 (134 mg, 100%) as an
inseparable 1:1 Z/E mixture as a colorless syrup. Data obtained
from the mixture: Rf (EtOAc/hexane 1:4): 0.28. Anal. Calcd
for C26H28O4S: 74.25 C, 6.71 H, 7.62 S. Found: 74.26 C, 6.74
H, 7.65 S. 17E: 1H NMR (CDCl3, 400 MHz) δ 7.36-7.25 (m,
15H), 6.24 (d, J ) 15, 1H), 6.00 (ddd, J ) 15.0, 7.5, 7.5, 1H),
4.67-4.49 (m, 4H), 3.87-3.84 (m, 1H), 3.70-3.53 (m, 3H),
2.66-2.64 (m, 1H), 2.54-2.43 (m, 1H), 2.44 (d, J ) 5.2, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 138.4-124.5, 128.6, 125.4,
79.0, 73.6, 72.3, 71.5, 71.2, 34.1. 17Z: 1H NMR (CDCl3, 400
MHz) δ 7.36-7.25 (m, 15H), 6.31 (d, J ) 11.0, 1H), 5.94 (ddd,
J ) 11.0, 7.2, 7.2, 1H), 4.67-4.49 (m, 4H), 3.89-3.86 (m, 1H),
3.70-3.53 (m, 3H), 2.66-2.64 (m, 1H), 2.54-2.43 (m, 1H), 2.49
(d, J ) 4.8, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 138.3-124.2,
128.5, 125.4, 78.8, 73.6, 72.5, 71.7, 71.1, 30.0.
Procedure for Electrophile-Induced Cyclization.
Method A. To a 0.5 M solution of alkene (0.16 mmol) in
CH3CN was added NaHCO3 (0.24 mmol). The mixture was
cooled to -30 °C and left to stir at this temperature for 5 min.
NIS (0.24 mmol) was then added and the reaction mixture
stirred for several hours. The reaction temperature was left
to increase depending on the reactivity of the substrate (-30
°C to room temperature). The mixture was diluted with
dichloromethane and washed with a saturated solution of
Na2S3O3. The combined aqueous layer was extracted with
dichloromethane. The combination of organic layers was dried
with MgSO4 and concentrated. The residue was purified by
chromatographic techniques.
Method B. IDCP (0.35 mmol) was added to a 0.5 M solution
of alkene (0.16 mmol) at -30 °C in CH3CN. The reaction
temperature was left to increase depending on the reactivity
of the substrate (-30 °C to room temperature). The mixture
was diluted with dichloromethane and washed with a satu-
rated solution of Na2S3O3. The combined aqueous layer was
extracted with dichloromethane. The combination of organic
layers was dried with MgSO4 and concentrated. The residue
was purified by chromatographic techniques.
Phenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-thio-r/â-D-
allo-pyranoside (18). The title compound was obtained
following cyclization method A from 2 (202 mg, 0.38 mmol),
dry NaHCO3 (48.3 mg, 0.55 mmol), NIS (141 mg, 0.57 mmol)
in dry CH3CN (900 µL) from -30 °C to room temperature for
15 h. TLC (EtOAc/hexane 1:3). Radial chromatography (from
hexane to EtOAc/hexane 1:3) afforded 18 (194 mg, 77%) as an
inseparable 1:9 R/â anomeric mixture as a yellowish syrup.
18â (obtained pure from pure 2E): Rf (EtOAc/hexane 1:3):
0.39. [R]20D +16.8 (c 0.89 CH2Cl2). 1H NMR (CDCl3, 400 MHz)
δ 7.62-7.22 (m, 20H), 5.12 (d, J ) 10.8, 1H), 4.92 (d, J ) 10.4,
1H), 4.76 (d, J ) 10.4, 1H), 4.63 (d, J ) 11.2, 1H), 4.60 (d, J )
12, 1H), 4.53 (d, J ) 11.2, 1H), 4.51 (d, J ) 12.0, 1H), 4.20-
4.16 (m, 2H), 4.02 (dd, J ) 10.8, 2.4, 1H), 3.78-3.62 (m, 3H).
13C NMR (CDCl3, 100.6 MHz) δ 138.6-137.8, 133.4-127.7,
84.6, 79.0, 76.4, 76.1, 75.9, 73.6, 72.4, 69.5, 32.0. Anal. Calcd
for C33H33IO4S: 60.74 C, 5.10 H, 4.91 S. Found: 60.96 C, 5.13
H, 4.97 S. 18R (data obtained from the spectrum of mixture):
1H NMR (CDCl3, 400 MHz) δ 7.62-7.20 (m, 20H), 5.41 (d, J
) 5.6, 1H), 4.99 (d, J ) 11.6, 1H), 4.87 (d, J ) 11.6, 1H), 4.65-
4.58 (m, 2H), 4.52 (d, J ) 10.4, 2H), 4.42 (d, J ) 11.2, 1H),
4.40 (d, J ) 12.0, 1H), 4.09 (m, 1H), 3.86-3.80 (m, 2H), 3.70
(m, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 138.6-127.5, 90.2,
78.4, 76.6, 75.8, 73.6, 72.2, 69.0, 67.8, 27.0.
N-(3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-r/â-D-allo-pyrano-
syl)succinimide (19). As described in cyclization method A,
compound 2 (216 mg, 0.41 mmol), NIS (150.7 mg, 0.62 mmol),
and 4Å MS (293 mg) in dry CH2Cl2 (900µL) were left to react
from -78 °C to room temperature for 19.5 h. TLC (EtOAc/
hexane 1:3). Radial chromatography (from hexane to EtOAc/
hexane 1:3) rendered compound 19 (169 mg, 64%) as an
inseparable 1:41 R/â anomeric mixture as a yellow foam. Data
obtained from the mixture: Rf (EtOAc/hexane 1:3): 0.07. Anal.
(Z/E)-4,6-Di-O-benzyl-1,2,3-trideoxy-1-phenylsulfanyl-
D-ribo-hex-1-enitol (17). As described in the general proce-
dure, the title compound was synthesized by reaction of 11
(100 mg, 0.31 mmol), diphenyl (phenylthiomethyl)phosphine
oxide (400 mg, 31.24 mmol), and n-BuLi (0.81 mL of 1.6 M
10306 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
Calcd for C31H32INO6: 58.04 C, 5.03 H, 2.18% N. Found 58.09
C, 5.02 H, 2.20% N. 19â: 1H NMR (CDCl3, 400 MHz) δ 7.38-
7.24 (m, 15H), 5.81 (d, J ) 11.2, 1H), 5.63 (dd, J ) 11.2, 11.2,
1H), 4.68 (d, J ) 3, 2H), 4.50 (s, 2H), 4.47 (s, 2H), 4.27 (m,
1H), 3.94 (dd, J ) 11.2, 3.0, 1H), 3.67 (m, 1H), 3.64 (dd, J )
10.8, 5.6, 1H), 3.59 (dd, J ) 10.8, 4.8, 1H), 2.70 (s, 4H). 13C
NMR (CDCl3, 100.6 MHz) δ 175.9, 138.1-137.4, 128.7-127.8,
80.1, 80.0, 75.8, 73.8, 73.1, 72.3, 72.2, 69.9, 28.6, 28.0.
Phenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-thio-r-D-
manno-pyranoside (20). As described in cyclization method
A, the title compound was synthesized starting from 4 (Z/E
ratio 1:3) (116.3 mg, 0.22 mmol), dry NaHCO3 (27.8 mg, 0.33
mmol), and NIS (81.1 mg, 0.33 mmol) in dry CH3CN (300 µL)
at -30 °C for 3 h. TLC (EtOAc/hexane 1:3). Radial chroma-
tography (from hexane to EtOAc/hexane 1:3) furnished 20 (52
mg, 36%) as a yellowish syrup. Rf (EtOAc/hexane 1:3): 0.51.
[R]20D +68 (c 0.02 CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 7.46-
7.19 (m, 20H), 5.78 (s, 1H), 4.89 (d, J ) 10.8, 1H), 4.87 (d, J )
3.6, 1H), 4.72 (d, J ) 11.6, 1H), 4.71 (d, J ) 11.6, 1H), 4.55 (d,
J ) 11.6, 1H), 4.52 (d, J ) 10.8, 1H), 4.48 (d, J ) 11.6, 1H),
4.42 (m, 1H), 3.99 (dd, J ) 8.8, 8.4, 1H), 3.86 (dd, J ) 10.8,
4.8, 1H), 3.73 (dd, J ) 10.8, 2, 1H), 3.10 (dd, J ) 8.4, 3.6, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 138.5-134.1, 132.2-127.7,
89.8, 77.8, 76.5, 75.6, 73.6, 71.3, 69.0, 35.0. Anal. Calcd for
C33H33IO4S: 60.74 C, 5.10 H, 4.91 S. Found: 60.70 C, 5.10 H,
4.94 S.
Phenyl 2-Deoxy-2-iodo-3,4:6,7-di-O-isopropylidene-1-
thio-D-glycero-r/â-D-talo-heptopyranoside (23). (A) From
13E. According to method B, cyclization was carried out
starting from compound 13E (350 mg, 0.95 mmol) and IDCP
(981 mg, 2.09 mmol) in dry CH3CN from -45 to -30 °C for 2
h. Control by TLC (EtOAc/hexane 1:4). The mixture was
purified by radial chromatography (from hexane to EtOAc/
hexane 1:3) to afford 23r (453 mg, 97%) as a white foam. (B)
From 13Z/E. Compound 13 (Z:E ratio 1:6) (360 mg, 0.98 mmol,
1eq) was treated with IDCP (1.01 g, 2.16 mmol) in dry CH3CN
(20 mL) from -45 °C to room temperature for 1.5 h to afford
23r product (233 mg, 48%) as a white foam. (C) From 13Z/E
and Long Reaction Times. Compound 13 (Z:E ratio 1:6) (360
mg, 0.98 mmol) was treated with IDCP (1.01 g, 2.16 mmol) in
dry CH3CN (20 mL) from -30 °C to room temperature for 3.5
h to furnsih 23r (60 mg, 41%) as a white foam, 23â (28 mg,
19%) as a yellowish syrup, and the corresponding 2-iodo-
pyranose (19 mg, 19%) as a pale yellow syrup. 23r: Rf (EtOAc/
hexane 1:4): 0.14. [R]20 +109.9 (c 1.25, CH2Cl2). 1H NMR
D
(CDCl3, 400 MHz) δ 7.52-7.50 (m, 2H), 7.34-7.25 (m, 3H),
5.59 (d, J ) 9.6, 1H), 4.68 (dd, J ) 7.9, 2.4, 1H), 4.40 (dd, J )
7.9, 1.6, 1H), 4.18 (m, 1H), 4.04 (dd, J ) 9.6, 2.4, 1H), 3.98
(dd, J ) 8.4, 6.2, 1H), 3.90 (dd, J ) 8.4, 4.4, 1H), 3.61 (dd, J )
8.4, 1.6, 1H), 1.50 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.34 (s,
3H). 13C NMR (CDCl3, 100.6 MHz) δ 133.4, 132.1, 129.1, 127.7,
109.6, 109.5, 90.1, 76.5, 73.9, 73.0, 69.8, 66.9, 27.1, 26.2, 25.3,
25.2, 21.2. Anal. Calcd for C19H25IO5S: 46.35 C, 5.12 H, 6.51
S. Found: 46.25 C, 5.09 H, 6.54 S. 23â: Rf (EtOAc/hexane
1:4): 0.13. (spectroscopic data obtained from the mixture) 1H
NMR (CDCl3, 400 MHz) δ 7.52-7.24 (m, 5H) 5.09 (d, J ) 4.4,
1H), 4.83 (dd, J ) 4.5, 5.2, 1H), 4.51 (dd, J ) 8.0, 3.6, 1H),
4.39 (dd, J ) 8.0, 2.4, 1H), 4.34 (dd, J ) 6.6, 5.2, 1H), 4.09 (m,
2H), 3.72 (dd, J ) 6.6, 2.4, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.39
(s, 3H), 1.37 (s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ 137.1,
131.3, 129.2, 127.5, 110.5, 109.5, 88.2, 74.1, 74.5, 74.3, 73.1,
66.9, 27.5, 26.1, 25.5, 24.7, 21.8.
Phenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-thio-r-D-
talo-pyranoside (24) and Phenyl 3,4,6-Tri-O-benzyl-2-
deoxy-2-iodo-1-thio-â-d-galacto-pyranoside (25). Com-
pound 14 (Z/E ratio 1:7) (89 mg, 0.35 mmol) was treated with
IDCP (174.2 mg, 0.37 mmol) in dry CH2Cl2 (390 µL) at -78
°C for 2.5 h. The reaction was monitored by TLC (EtOAc/
hexane 1:3). After the standard workup described in method
B, radial chromatography (from hexane to EtOAc/hexane 1:3)
afforded 24 (22 mg, 20%) and 25 (16 mg, 15%) as a yellowish
syrups. 24: Rf (EtOAc/hexane 1:3): 0.48. 1H NMR (CDCl3, 400
MHz) δ 7.48-7.21 (m, 20H), 5.91 (s, 1H), 5.07 (d, J ) 12.0,
1H), 4.76 (d, J ) 11.2, 1H), 4.69 (m, 1H), 4.61-4.38 (m, 5H),
3.98 (m, 1H), 3.73-3.71 (m, 2H), 3.38 (m, 1H). 13C NMR
(CDCl3, 100.6 MHz) δ 138.1, 132.3-127.6, 90.3, 74.6, 73.8, 73.7,
73.6, 72.3, 71.0, 69.3, 25.0. Anal. Calcd for C33H33IO4S: 60.74
C, 5.10 H, 4.91 S. Found: 60.70 C, 5.10 H, 4.91 S. 25:
decomposes on standing. Rf (EtOAc/hexane 1:3): 0.43. 1H NMR
(CDCl3, 400 MHz) δ 7.59-7.17 (m, 20H), 4.87 (d, J ) 10.8,
1H), 4.83 (d, J ) 11.6, 1H), 4.71 (d, J ) 11.2, 1H), 4.64 (d, J )
11.2, 1H), 4.49 (d, J ) 11.6, 1H), 4.48 (d, J ) 11.2, 1H), 4.42
(d, J ) 11.2, 1H), 4.29 (app. t, J ) 10.8, 1H), 3.83 (m, 1H),
3.71-3.67 (m, 1H) 3.65-3.60 (3H, m, 3H). 13C NMR (CDCl3,
100.6 MHz) δ 138.6-137.3, 133.2-127.7, 89.2, 85.4, 77.9, 74.6,
73.8, 73.1, 72.9, 68.6, 33.1.
2,3-Bis-benzyloxy-4-benzyloxymethyl-2-(1-iodo-2-phenyl-
sulfanyl-ethyl)-oxetane (21). A suspension of KH 30% (70.2
mg, 0.52 mmol) in dry ether (1.8 mL) was added dropwise to
a solution of 4 (Z/E ratio 1:2) (103 mg, 0.19 mmol) in dry ether
(2.9 mol) at 0 °C, and the resulting mixture was allowed to
stir for 30 min until complete formation of the alcoholate. The
mixture was cooled to -78 °C and a solution of iodine (187
mg, 0.74 mmol) in dry Et2O (1.5 mL) was then added. The
reaction mixture was allowed to stir from -78 °C to room
temperature for 1.5 h. TLC (EtOAc/hexane 1:3). A solution of
Na2S3O3 was then added and the reaction product was
extracted with ether. The combination of the etheral layers
was concentrated and the residue purified by radial chroma-
tography (from hexane to EtOAc/hexane 1:3) to afford 21 (39
mg, 31%) as a yellowish syrup. Rf (EtOAc/hexane 1:3): 0.38.
1
[R]20 -2.34 (c 1.57, CH2Cl2,). H NMR (CDCl3, 400 MHz) δ
D
7.41-7.12 (m, 20H), 5.26 (d, J ) 12.0, 1H), 5.12 (d, J ) 12.0,
1H), 5.00 (d, J ) 11.6, 1H), 4.60 (d, J ) 11.6, 1H), 4.42-4.40
(m, 1H), 4.38 (s, 2H), 4.36-4.31 (m, 2H), 3.62 (dd, J ) 15.0,
2.6, 1H), 3.45 (dd, J ) 11.4, 2.6 Hz, 1H), 3.34 (dd, J ) 11.4,
3.8 Hz, 1H), 3.22 (dd, J ) 15.0, 10.2, 1H). 13C NMR (CDCl3,
100.6 MHz) δ 138.8-135.4, 129.5-126.4, 108.3, 81.4, 81.1,
73.5, 69.5, 67.1, 37.6, 37.2. Anal. Calcd for C33H33IO4S: 60.74
C, 5.10 H, 4.91 S. Found: 60.75 C, 5.11 H, 4.90 S.
Phenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-thio-r/â-D-
gulo-pyranoside (22). As described in cyclization method B,
compound 22 (611 mg, 77%, R/â ratio 1:12, inseparable
mixture) was obtained as a yellowish syrup starting from
compound 12 (Z:E ratio 1:10) (640 mg, 1.2 mmol) and IDCP
(1.25 g, 2.67 mmol) in dry CH3CN (17 mL), at -30 °C for 3 h.
The reaction was monitored by TLC (EtOAc/hexane 1:3). The
reaction mixture was purified by radial chromatography (from
hexane to EtOAc/hexane 1:3). Data obtained from the mixture.
Rf (EtOAc/hexane 1:4): 0.47. Anal. Calcd for C33H33IO4S: 60.74
C, 5.10 H, 4.91 S. Found: 60.68 C, 5.11 H, 5.00 S. 22â:1H NMR
(CDCl3, 400 MHz) δ 7.61-7.18 (m, 20H), 5.13 (d, J ) 11.2,
1H), 4.69-4.36 (m, 6H), 4.44 (dd, J ) 11.2, 2.8, 1H), 4.23 (td,
J ) 1.2, 6.4, 6.4, 1H), 3.81 (dd, J ) 3.4, 2.8, 1H), 3.57 (m, J )
9.6, 9.6, 6.4, 2H), 3.37 (dd, J ) 3.4, 1.2, 1H). 13C NMR (CDCl3,
100.6 MHz) δ 138.0-127.6, 85.0, 78.1, 74.9, 74.0, 73.6, 73.3,
Phenyl 6-O-tert-Butyldiphenylsilyl-2-deoxy-2-iodo-3,4-
O-isopropylidene-1-thio-r/â-D-talo-pyranoside (26). Com-
pound 15 (Z/E ratio 1:8) (103.8 mg, 0.19 mmol) was treated
with dry NaHCO3 (24.5 mg, 0.29 mmol) and NIS (71.3 mg,
0.29 mmol) in dry CH3CN (500 µL) at -30 °C for 15 h. The
reaction was monitored by TLC (EtOAc/hexane 1:3). After the
standard workup described in method A, radial chromatogra-
phy (from hexane to EtOAc/hexane 1:3) rendered 26 (71 mg,
55%) as an inseparable 42:1 R/â mixture as a yellowish syrup.
Data extracted from the mixture. Rf (EtOAc/hexane 1:3): 0.53.
Anal. Calcd for C31H37IO4SSi: 56.36 C, 5.64 H, 4.85 S. Found:
56.34 C, 5.61 H, 4.87 S. 26R: 1H NMR (CDCl3, 400 MHz) δ
1
72.6, 68.9, 31.3. 22R: Rf (EtOAc/hexane 1:4): 0.47. H NMR
(CDCl3, 400 MHz) δ 7.54-7.20 (m, 20H), 5.41 (d, J ) 5.2, 1H),
5.06 (dd, J ) 5.2, 2.8, 1H), 4.89 (s, 1H), 4.80-4.36 (m, 6H),
3.73 (d, J ) 2.8, 1H), 3.63-3.54 (m, 2H), 3.48 (bs, 1H). 13C
NMR (CDCl3, 100.6 MHz) δ 138.2-127.1, 89.7, 77.4, 75.0, 73.5,
73.3, 73.1, 69.2, 66.3, 28.0.
J. Org. Chem, Vol. 70, No. 25, 2005 10307

Rodr´ıguez et al.
7.71-7.21 (m, 15H), 5.52 (d, J ) 9.6, 1H), 4.65 (dd, J ) 7.6,
2.4, 1H), 4.31 (dd, J ) 7.6, 1.2, 1H), 4.05 (dd, J ) 9.6, 2.4,
1H), 3.89 (m, 1H), 3.82-3.72 (m, 2H), 1.42 (s, 3H), 1.35 (s, 3H),
1.04 (s, 9H). 13C NMR (CDCl3, 100.6 MHz) δ 135.9-133.4,
129.9-127.8, 109.7, 89.9, 77.0, 74.4, 70.0, 62.5, 27.0, 26.3, 25.5,
22.4, 19.4.
1H), 4.87 (d, J ) 9.0, 1H), 4.77 (d, J ) 10.4, 1H), 4.64-4.49
(m, 4H), 4.17-4.09 (m, 2H), 4.02 (dd, J ) 9.0, 2.8, 1H), 3.73-
3.64 (m, 3H), 4.48 (m, 1H), 2.40-0.67 (m, 43H). 13C NMR
(CDCl3, 100.6 MHz) δ 140.8, 138.5-137.7, 128.6-126.8, 122.0,
99.3, 79.9, 78.6, 76.9, 75.8, 73.5, 73.1, 72.4, 69.5, 56.9-12.0,
33.3.
Phenyl 2-Deoxy-2-iodo-3,4-O-isopropylidene-1-thio-r/
â-D-erythro-pyranoside (27). Compound 17 (Z/E ratio 2:3)
(35 mg, 0.13 mmol) was treated with IDCP (135.1 mg, 0.29
mmol) in dry CH3CH2CN (300 µL) at -78 °C for 23 h. The
reaction was monitored by TLC (EtOAc/hexane 1:1). After the
standard workup described in method B, radial chromatogra-
phy (from hexane to EtOAc/hexane 1:1) afforded 27 (17 mg,
33%) as an inseparable 1.1:1 R/â mixture as a yellowish syrup.
Data extracted from the mixture. Rf (EtOAc/hexane 1:1): 0.56.
Anal. Calcd for C14H17IO3S: 42.87 C, 4.37 H, 8.17 S. Found:
42.85 C, 4.38 H, 8.20 S. 27r: 1H NMR (CDCl3, 400 MHz) δ
7.58-7.25 (m, 5H), 5.33 (d, J ) 10.4, 1H), 4.59 (m, 1H), 4.32
(m, 1H), 4.27 (m, 1H), 4.08 (dd, J ) 10.4, 2.8, 1H), 3.89 (dd, J
) 9.6, 4, 1H), 1.54 (s, 3H), 1.49 (s, 3H). 13C NMR (CDCl3, 100.6
MHz) δ 132.8, 129.4-128.2, 109.5, 88.3, 76.5, 71.7, 64.0, 28.4,
27.2, 22.9. 27â: 1H NMR (CDCl3, 400 MHz) δ 7.58-7.25 (m,
5H), 5.09 (d, J ) 7.6, 1H), 4.59 (m, 1H), 4.27 (m, 1H), 4.15
(dd, J ) 7.6, 6.8, 1H), 3.92 (dd, J ) 12.4, 4.0, 1H), 3.58 (dd, J
) 12.4, 4.0, 1H), 1.38 (s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3,
100.6 MHz) δ 133.2, 129.4-128.2, 110.8, 88.5, 80.3, 72.8, 64.1,
29.7, 26.4, 25.7.
General Procedure of Glycosylation. A solution of the
glycosyl donor (1 mmol) and the glycosyl acceptor (2 mmol) in
CH2Cl2 (4 mL) was stirred with 4Å molecular sieves for 2 h.
The mixture was then cooled to -78 °C, and NIS (3 mmol)
and TfOH (0.2 mmol) were added. The mixture was allowed
to warm to -40 °C and stirred until the reaction had finished.
The reaction mixture was then diluted with CH2Cl2 and
washed with a solution of Na2S3O3. The ethereal layer was
dried with Na2SO4 and concentrated. The residue was then
purified by radial chromatography.
Methyl (3′,4′,6′-Tri-O-benzyl-2′-deoxy-2′-iodo-r/â-D-allo-
pyranosyl)-(1f2)-3-O-benzyl-4,6-O-benzylidene-r-D-gluco-
pyranoside (30a). According to the general glycosylation
conditions, 18 (R/â ratio 1:9) (80.9 mg, 0.12 mmol), NIS (66.8
mg, 0.27 mmol), 29a (92.3 mg, 0.25 mmol), 4Å MS (120 mg),
and TfOH (1 drop) in dry CH2Cl2 (3 mL) were allowed to react
at -78 °C for 1 h and then at -40 °C for 2.5 h. The reaction
progress was monitored by TLC (EtOAc/hexane 1:3). Radial
chromatography (from hexane to EtOAc/hexane 1:3) afforded
30a (84 mg, 74%) as an inseparable 1:6 R/â mixture as a white
solid. Data extracted from the mixture. Rf (EtOAc/hexane
1:3): 0.23. Anal. Calcd for C48H51IO10: 63.02 C, 5.62 H.
Found: 62.96 C, 5.64 H. 30aâ: 1H NMR (CDCl3, 400 MHz) δ
7.52-7.05 (m, 25H), 5.54 (s, 1H), 5.08 (d, J ) 9.2, 1H), 5.07
(d, J ) 10.8, 1H), 4.93 (d, J ) 3.2, 1H), 4.89 (d, J ) 10.4, 1H),
4.79 (d, J ) 10.8, 1H), 4.78 (d, J ) 10.4, 1H), 4.65-4.47 (m,
4H), 4.27 (dd, J ) 9.5, 4.4, 1H), 4.17-4.10 (m, 3H), 4.00 (app.
t, J ) 9.2, 1H), 3.90-3.78 (m, 1H), 4.75-3.67 (m, 5H), 3.59
(app. t, J ) 9.2, 1H), 3.38 (s, 3H). 13C NMR (CDCl3, 100.6 MHz)
δ 139.0-137.7, 129.2-126.3, 102.1, 101.6, 100.6, 82.8, 80.3,
78.8, 77.7, 76.8, 76.0, 75.6, 73.8, 73.2, 72.6, 69.8, 69.5, 62.4,
55.6, 30.9.
Cholesteryl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-r/â-D-
allo-pyranoside (30b). Following the general glycosylation
procedure, 18 (R/â ratio 1:9) (100 mg, 0.15 mmol), NIS (82.6
mg, 0.34 mmol), cholesterol (118.5 mg, 0.31 mmol), 4Å MS (150
mg), and TfOH (1 drop) in dry CH2Cl2 (3.5 mL) were allowed
to react at -78 °C for 1 h and then at -40 °C 2.5 h. The
reaction was monitored by TLC (EtOAc/hexane 1:3). Radial
chromatography (from hexane to EtOAc/hexane 1:3) provided
30b (115 mg, 81%) as an inseparable 1:9 R/â mixture as a
yellow foam. Data obtained from the mixture: Rf (EtOAc/
hexane 1:3): 0.53. Anal. Calcd for C54H73IO5: 69.81 C, 7.92
H. Found: 69.68 C, 7.89 H. 30bâ: 1H NMR (CDCl3, 400 MHz)
δ 7.52-7.22 (m, 15H), 5.35 (d, J ) 4.8, 1H), 4.88 (d, J ) 10.4,
Methyl
(3′,4′,6′-Tri-O-benzyl-2′-deoxy-2′-iodo-r/â-D-
manno-pyranosyl)-(1f2)-3-O-benzyl-4,6-O-benzylidene-
r-D-gluco-pyranoside (31a). As described in the general
glycosylation procedure, 20 (37.3 mg, 0.06 mmol), NIS (30.8
mg, 0.13 mmol), 29a (42.6 mg, 0.11 mmol), 4Å MS (60 mg),
TfOH (1 drop) in dry CH2Cl2 (1.4 mL) were allowed to react
at -78 °C for 1 h and then at -40 °C for 2 h. The reaction
progress was monitored by TLC (EtOAc/hexane 1:3). Radial
chromatography (from hexane to EtOAc/hexane 1:3) afforded
31a (37 mg, 71%) as an inseparable 45:1 R/â mixture as a white
crystalline solid. Data extracted from the mixture. Rf (EtOAc/
hexane 1:3): 0.24. Anal. Calcd for C48H51IO10: 63.02 C, 5.62
H. Found: 63.16 C, 5.65 H. 31ar: 1H NMR (CDCl3, 400 MHz)
δ 7.49-6.99 (m, 25H), 5.53 (s, 1H), 5.38 (s, 1H), 4.88 (d, J )
10.4, 1H), 4.89 (d, J ) 3.2, 1H), 4.72 (d, J ) 10.8, 1H), 4.69 (d,
J ) 11.6, 1H), 4.68-4.62 (m, 3H), 4.50 (d, J ) 11.6, 1H), 4.48
(d, J ) 10.8, 1H), 4.35 (d, J ) 12.0, 1H), 4.29 (dd, J ) 9.6, 4.0,
1H), 4.20 (dd, J ) 9.6, 2.8, 1H), 3.97 (dd, J ) 9.0, 9.0, 1H),
3.89-3.85 (m, 2H), 4.79 (dd, J ) 10.0, 4.4, 1H), 3.74-3.53 (m,
3H), 3.58-3.53 (m, 1H), 3.44 (s, 1H), 3.38 (dd, J ) 8.4, 4, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 138.8-137.5, 128.9-126.1,
101.4, 98.3, 97.1, 82.2, 77.1, 76.8, 75.9, 75.4, 74.0, 73.1, 72.1,
71.0, 69.1, 68.6, 62.4, 55.4, 33.5.
Cholesteryl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-r/â-D-
manno-pyranoside (31b). According to the general glycosyl-
ation procedure, 20 (22.1 mg, 0.034 mmol) was treated with
NIS (18.3 mg, 0.075 mmol), cholesterol (26.2 mg, 0.068 mmol),
4Å MS (34 mg), and TfOH (1drop) in dry CH2Cl2 (800 µL). The
reaction mixture was stirred at -78 °C for 1 h and then at
-40 °C 2 h. TLC (EtOAc/hexane 1:3). Radial chromatography
(from hexane to EtOAc/hexane 1:3) provided 31b (23 mg, 72%)
as an inseparable 37:1 R/â mixture as a yellowish foam. Data
extracted from the mixture. Rf (EtOAc/hexane 1:3): 0.63. Anal.
Calcd for C54H73IO5: 69.81 C, 7.92 H. Found: 69.79 C, 7.92
H. 31br: 1H NMR (CDCl3, 400 MHz) δ 7.50-7.15 (m, 15H),
5.38 (s, 1H), 5.28 (d, J ) 5.2, 1H), 4.85 (d, J ) 10.8, 1H), 4.71
(dd, J ) 11.6, 1H), 4.58-4.46 (m, 4H), 3.96-3.88 (m, 2H), 4.81
(dd, J ) 10.8, 4.4, 1H), 3.71 (dd, J ) 10.8, 1.6, 1H), 4.48 (m,
1H), 3.36 (dd, J ) 8.0, 4.0, 1H), 3.35-0.67 (m, 43H). 13C NMR
(CDCl3, 100.6 MHz) δ 140.5, 138.5-138.0, 129.2-127.2, 122.2,
99.6, 77.5, 77.2, 76.1, 75.5, 73.4, 72.2, 71.0, 69.0, 56.2-12.0,
34.6.
Methyl (3′,4′,6′-Tri-O-benzyl-2′-deoxy-2′-iodo-r/â-D-gulo-
pyranosyl)-(1f2)-3-O-benzyl-4,6-O-benzylidene-r-D-gluco-
pyranoside (32a). According to the general glycosylation
procedure, the title compound was prepared starting from 22
(R:â ratio 10:1 or 1:5) (55 mg, 0.08 mmol), NIS (42 mg, 0.18
mmol), 29a (63 mg, 0.17 mmol), 4Å MS (80 mg), and TfOH (1
drop) in dry CH2Cl2 (2.1 mL, 0.04 M). The reaction mixture
was stirred at -78 °C for 1 h and then at -40 °C for 3 h. TLC
(EtOAc/hexane 1:3). Radial chromatography (from hexane to
EtOAc/hexane 1:3) furnished 32a (49 mg, 62%) as an insepa-
rable 1:12 R/â mixture as a transparent syrup. Data extracted
from the mixture. Rf (EtOAc/hexane 1:3): 0.31. Anal. Calcd
for C48H51IO10: 63.02 C, 5.62 H. Found: 63.17 C, 5.60 H.
32aâ: 1H NMR (CDCl3, 400 MHz) δ 7.49-7.16 (m, 20H), 5.54
(s, 1H), 5.08 (d, J ) 9.2, 1H), 5.07 (d, J ) 10.8, 1H), 4.86 (d, J
) 3.8, 1H), 4.80 (d, J ) 10.8, 1H), 4.65 (d, J ) 11.2, 1H), 4.44
(m, 6H), 4.28 (dd, J ) 10.0, 4.8, 1H), 4.16 (td, J ) 6.6, 1.2,
1H), 4.03 (dd, J ) 9.6, 9.2, 1H), 3.85 (ddd, J ) 10.0, 9.6, 4.8,
1H), 3.80 (dd, J ) 3.6, 3.0, 1H), 3.75 (dd, J ) 9.6, 3.8, 1H),
3.72 (app. t, J ) 10.0, 1H), 3.59 (dd, J ) 9.6, 9.2, 1H), 3.53 (d,
J ) 6.6, 2H), 3.39 (s, 3H), 3.36 (dd, J ) 3.6, 1.2, 1H). 13C NMR
(CDCl3, 100.6 MHz) δ 138.9-126.2, 101.5, 101.4, 100.4, 82.8,
79.2, 79.1, 77.8, 75.3, 74.2, 73.9, 73.5, 73.0, 72.8, 69.4, 69.0,
62.3, 55.5, 30.8.
10308 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2-Deoxy-2-iodo-glycosides from Furanoses
Cholesteryl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-r/â-D-
gulo-pyranoside (32b). Following the general glycosylation
procedure, 22 (R:â ratio2:7) (120 mg, 0.18 mmol), NIS (91 mg,
0.40 mmol), cholesterol (142 mg, 0.37 mmol), 4Å molecular
sieves (160 mg), and TfOH (1 drop) in dry CH2Cl2 (6.1 mL)
were allowed to react at -78 °C for 1 h and then at -40 °C for
3 h. TLC (EtOAc/hexane 1:3). Radial chromatography (from
hexane to EtOAc/hexane 1:3) afforded 32b (113 mg, 66%) as
an inseparable 1:8 R:â mixture as a pale yellow solid. Data
extracted from the mixture. Rf (EtOAc/hexane 1:3): 0.62. Anal.
Calcd for C54H73IO5: 69.81 C, 7.92 H. Found: 69.87 C, 7.89
H. 32bâ: 1H NMR (CDCl3, 400 MHz) δ 7.36-7.18 (m, 15H),
5.34 (bs, 1H), 4.82 (d, J ) 9.2, 1H), 4.65 (d, J ) 11.6, 1H), 4.43
(m, 6H), 4.16 (t, J ) 6.4, 1H), 3.79 (dd, J ) 3.6, 3.2, 1H), 3.56
(d, J ) 6.4, 2H), 3.49 (m, 1H), 3.34 (d, J ) 3.2, 1H), 2.39-0.67
(m, 44H). 13C NMR (CDCl3, 100.6 MHz) δ 140.9-127.8, 121.9,
98.9, 79.7, 76.0, 74.1, 73.8, 73.5, 72.9, 72.8, 69.1, 57.0-12.1,
33.5.
Methyl (2′-Deoxy-2′-iodo-3′,4′:6′,7′-di-O-isopropylidene-
D-glycero-r/â-D-talo-heptopyranosyl)-(1f2)-3-O-benzyl-
4,6-O-benzylidene-r-D-gluco-pyranoside (33a). As de-
scribed in the glycosylation procedure, the title compound was
prepared starting from 23r (200 mg, 0.40 mmol), NIS (201
mg, 0.89 mmol), 29a (302 mg, 0.81 mmol), 4Å MS (200 mg),
and TfOH (7 µL, 0.08 mmol) in dry CH2Cl2 (13 mL). The
reaction mixture was stirred at -78 °C for 1 h and then at
-60 °C for 1 h. TLC (EtOAc/hexane 1:3). Radial chromatog-
raphy (from hexane to EtOAc/hexane 1:3) of the crude provided
33a (210 mg, 69%) as an inseparable 40:1 R:â mixture as a
white solid. Data extracted from the mixture. Rf (EtOAc/
hexane 1:3): 0.30. Anal. Calcd for C34H43IO11: 54.12 C, 5.74
H. Found: 53.89 C, 5.75 H. 33ar: 1H NMR (CDCl3, 400 MHz)
δ 7.44-7.23 (m, 10H), 5.54 (s, 1H), 5.22 (d, J ) 7.2, 1H), 4.89
(d, J ) 4.0, 1H), 4.88 (d, J ) 12.2, 1H), 4.80 (d, J ) 12.2, 1H),
4.66 (dd, J ) 7.8, 2.4, 1H), 4.41 (dd, J ) 7.8, 2.0, 1H), 4.28
(dd, J ) 10.4, 4.6, 1H), 4.22 (dd, J ) 8.8, 3.6, 1H), 4.19 (ddd,
J ) 8.4, 3.6, 2.8, 1H), 4.02 (s, 1H), 3.99 (dd, J ) 8.8, 2.8, 1H),
3.96 (dd, J ) 7.2, 2.4 Hz, 1H), 3.87 (dd, J ) 9.6, 4.0, 1H), 3.83
(dd, J ) 9.8, 4.6, 1H), 3.73 (dd, J ) 10.4, 9.8, 1H), 3.61 (d, J )
9.6, 1H), 3.57 (dd, J ) 8.4, 2.0, 1H), 3.47 (s, 3H), 1.51 (s, 3H),
1.41 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H). 13C NMR (CDCl3, 100.6
MHz) δ 139.1, 137.5, 129.1, 128.4, 128.3, 128.2, 127.5, 126.3,
109.7, 109.6, 101.5, 100.2, 97.6, 82.3, 76.8, 76.4, 76.0, 74.9, 74.0,
73.4, 70.1, 69.3, 67.0, 62.6, 55.7, 27.3, 26.2, 25.2, 23.1.
Cholesteryl 2′-deoxy-2′-iodo-3′,4′:6′,7′-di-O-isopropyl-
idene-D-glycero-r/â-D-talo-heptopyranoside (33b). Accord-
ing to the general glycosylation procedure, 23r (200 mg, 0.40
mmol) was treated with NIS (201 mg, 0.89 mmol), cholesterol
(299 mg, 0.81 mmol), 4Å molecular sieves (200 mg), and TfOH
(7 µL, 0.08 mmol) in dry CH2Cl2 (13 mL) at -78 °C for 1 h
and then at -20 °C for 20 h. TLC (EtOAc/hexane 1:3). Radial
chromatography (from hexane to EtOAc/hexane 1:4) provided
33b (177 mg, 57%) as an inseparable 8:1 R:â mixture as a pale
yellow solid. Data extracted from the mixture. Rf (EtOAc/
hexane 1:3): 0.43. Anal. Calcd for C40H65IO6: 62.49 C, 8.52
H. Found: 62.26 C, 8.53 H. 33br: 1H NMR (CDCl3, 400 MHz)
δ 5.34 (bs, 1H), 5.20 (d, J ) 8.0, 1H), 4.64 (dd, J ) 7.8, 2.8,
1H), 4.37 (dd, J ) 7.8, 1.8, 1H), 4.22 (m, 1H), 4.09 (dd, J )
8.4, 6.0, 1H), 3.99 (dd, J ) 8.0, 2.8, 1H), 3.94 (dd, J ) 8.4, 4.4,
1H), 3.58 (dd, J ) 8.0, 1.8, 1H), 3.47 (m, 1H), 2.30-0.68 (m,
44H), 1.51 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H). 13C
NMR (CDCl3, 100.6 MHz) δ 140.9, 122.0, 109.7, 109.6, 100.4,
77.7, 76.6, 74.1, 73.6, 69.7, 67.3, 56.9-12.1, 27.3, 26.2, 25.2,
24.1, 21.3.
Methyl (6′-O-tert-Butyldiphenylsilyl-2′-deoxy-2′-iodo-
3′,4′-O-isopropylidene-r/â-D-talo-pyranosyl)-(1f2)-3-O-
benzyl-4,6-O-benzylidene-r-D-gluco-pyranoside (34a). Fol-
lowing the general glycosylation procedure, compound 26 (R/â
ratio 49:1) (58 mg, 0.09 mmol), NIS (47.3 mg, 0.19 mmol), 29a
(65.4 mg, 0.18 mmol), 4Å MS (88 mg), and TfOH (1 drop) in
dry CH2Cl2 (2 mL) were allowed to react at -78 °C for 1.5 h.
The reaction was monitored by TLC (EtOAc/hexane 1:3).
Radial chromatography (from hexane to EtOAc/hexane 1:3)
afforded 34a (48 mg, 59%) as an inseparable 20:1 R/â mixture
as a white crystalline solid. Data extracted from the mixture.
Rf (EtOAc/hexane 1:3): 0.38. Anal. Calcd for C46H55IO10Si:
59.86 C, 6.01 H. Found: 59.83 C, 5.98 H. 34ar: 1H NMR
(CDCl3, 400 MHz) δ 7.68-7.17 (m, 20H), 5.50 (s, 1H), 5.23 (d,
J ) 7.6, 1H), 4.89 (d, J ) 3.6, 1H), 4.77 (s, 2H), 4.64 (dd, J )
8, 2.8, 1H), 4.41 (dd, J ) 8, 2.0, 1H), 4.26 (dd, J ) 9.6, 4.8,
1H), 4.11 (dd, J ) 7.6, 2.8, 1H), 3.99-3.68 (m, 7H), 3.54 (dd,
J ) 9.6, 9.6, 1H), 3.47 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.03
(s, 9H). 13C NMR (CDCl3, 100.6 MHz) δ 139.2-137.6, 136.0-
126.3, 109.3, 101.5, 101.1, 98.1, 82.1, 77.2, 77.0, 76.5, 75.0, 73.7,
69.4, 69.3, 61.6, 61.9, 55.6, 27.1, 26.2, 25.2, 24.5, 19.5.
Cholesteryl 6-O-tert-Butyldiphenylsilyl-2-deoxy-2-iodo-
3,4-O-isopropylidene-r/â-D-talo-pyranoside (34b). As de-
scribed in the general glycosylation procedure, compound 26
(R/â ratio 42:1) (70 mg, 0.11 mmol), NIS (57.1 mg, 0.23 mmol),
cholesterol (82 mg, 0.21 mmol), 4Å MS (106 mg), and TfOH (1
drop) in dry CH2Cl2 (2.5 mL) were allowed to react at -78 °C
for 1.5 h. The reaction was monitored by TLC (EtOAc/hexane
1:3). Radial chromatography (from hexane to EtOAc/hexane
1:3) produced 34b (35.4 mg, 36%) as a 10:1 R/â mixture as a
yellowish syrup. Data extracted from the mixture. Rf (EtOAc/
hexane 1:3): 0.55. Anal. Calcd for C52H77IO5Si: 66.64 C, 8.28
H. Found: 66.61 C, 8.30 H. 34br: 1H NMR (CDCl3, 400 MHz)
δ in ppm: 7.71-7.26 (10H, m, Ar), 5.23 (d, J ) 7.2, 1H), 5.18
(d, J ) 4.0, 1H), 4.64-4.60 (m, 1H), 4.29-4.21 (m, 1H), 4.02-
3.98 (m, 1H), 3.92 (m, 1H), 3.88-3.72 (m, 2H), 3.50 (m, 1H),
2.27-0.67 (m, 58H). 13C NMR (CDCl3, 100.6 MHz) δ 148.4,
145.6, 140.7, 135.9-127.8, 122.0, 109.5, 100.2, 77.1, 75.1, 74.4,
68.8, 61.6, 56.9-12.1, 27.1, 26.3, 25.8, 24.8, 19.6.
Methyl (3′,4′-O-Isopropylidene-2′-deoxy-2′-iodo-r/â-D-
erythro-pyranosyl)-(1f2)-3-O-benzyl-4,6-O-benzylidene-
r-D-gluco-pyranoside (35a). According to the general gly-
cosylation conditions, compound 27 (R/â ratio 14:1) (80.1 mg,
0.20 mmol), NIS (110.1 mg, 0.45 mmol), 29a (152.1 mg, 0.41
mmol), 4Å MS (20 mg) and and TfOH (1 drop) in dry CH2Cl2
(4.7 mL) were allowed to react at -78 °C for 30 min. The
reaction was monitored by TLC (EtOAc/hexane 1:3). Radial
chromatography (from hexane to EtOAc/hexane 1:3) afforded
35a (59.4 mg, 44%) as an inseparable 1:3 R/â mixture as a
white solid. Data extracted from the mixture. Rf (EtOAc/
hexane 1:3): 0.17. Anal. Calcd for C29H35IO9: 53.22 C, 5.39
H. Found: 53.40 C, 5.41 H. 35ar: 1H NMR (CDCl3, 400 MHz)
δ 7.48-7.22 (m, 10H), 5.56 (s, 1H), 5.30 (d, J ) 7.6, 1H), 5.06
(d, J ) 10.8, 1H), 4.88-4.78 (m, 2H), 4.58 (dd, J ) 7.2, 3, 1H),
4.33-4.26 (m, 2H), 4.13 (m, 1H), 4.09-3.55 (m, 7H), 3.42 (s,
3H), 1.53 (s, 3H), 1.37 (s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ
138.9-137.5, 129.1-126.2, 109.3, 103.9, 101.4, 100.5, 82.3,
79.3, 77.8, 76.3, 75.5, 73.4, 69.2, 62.2, 61.5, 55.5, 26.7, 25.2,
21.9. 35aâ: 1H NMR (CDCl3, 400 MHz) δ 7.48-7.22 (m, 10H),
5.56 (s, 1H), 4.95 (d, J ) 4.0, 1H), 4.88-4.78 (m, 3H), 4.45
(dd, J ) 9.6, 6.0, 1H), 4.33-4.26 (m, 1H), 4.13 (m, 1H), 4.09-
3.55 (m, 8H), 3.50 (s, 3H), 1.53 (s, 3H), 1.37 (s, 3H). 13C NMR
(CDCl3, 100.6 MHz) δ 138.9-137.5, 129.1-126.2, 110.6, 103.4,
101.4, 98.5, 82.3, 80.6, 79.3, 77.3, 75.54, 73.1, 69.2, 62.7, 62.6,
55.7, 32.8, 28.1, 25.9.
Cholesteryl 3,4-O-Isopropylidene-2-deoxy-2-iodo-r/â-
D-erythro-pyranoside (35b). Following the general glycosyl-
ation procedure, compound 27 (R/â ratio 14:1) (53.2 mg, 0.14
mmol) was treated with NIS (73.1 mg, 0.30 mmol), cholesterol
(104.9 mg, 0.27 mmol), 4Å MS (14 mg), and TfOH (1drop) in
dry CH2Cl2 (3.3 mL) at -78 °C. The reaction temperature was
left to increase to 0 °C for 17 h. The reaction was monitored
by TLC (EtOAc/hexane 1:3). Radial chromatography (from
hexane to EtOAc/hexane 1:3) furnished 35b (42.1 mg, 46%)
as an inseparable 1:25 R/â mixture as a yellow foam. Data
extracted from the mixture. Rf (EtOAc/hexane 1:3): 0.5. Anal.
Calcd for C35H57IO4: 62.86 C, 8.59 H. Found: 62.80 C, 8.56
H. 1H NMR (CDCl3, 400 MHz) δ 5.35 (d, J ) 4.0, 1H), 4.63 (d,
J ) 8.8, 1H), 4.50 (dd, J ) 9.2, 5.6, 1H), 4.25 (dd, J ) 13.2,
2.8, 1H), 4.08 (m, 1H), 3.87-3.82 (m, 2H), 4.54-3.46 (m, 1H),
J. Org. Chem, Vol. 70, No. 25, 2005 10309

Rodr´ıguez et al.
2.37-0.67 (m, 43H), 1.53 (s, 3H), 1.37 (s, 3H). 13C NMR (CDCl3,
100.6 MHz) δ 140.8, 122.1, 101.2, 81.4, 79.4, 73.4, 63.0, 56.9-
12.1, 33.6, 28.4, 26.1.
Fellowship from DURSI (Generalitat de Catalunya to
O.B. and M.A.R. is gratefully acknowledged.
Supporting Information Available: NMR spectra of
compounds 2, 12, 13, 15, 18, 22, 23, 25, 30a, 30b, 32a, and
32b. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. Financial support from DGESIC
BQU2002-01188 (Ministerio de Ciencia y Tecnolog´ıa,
Spain) is acknowledged. Technical assistance from the
Servei de Recursos Cientifics (URV) is acknowledged.
JO051461B
10310 J. Org. Chem., Vol. 70, No. 25, 2005