2,3-Anhydrosugars in glycoside bond synthesis. Application to α-D-galactofuranosides

Article abstract of DOI:10.1021/jo061713o

We report here the use of 2,3-anhydro-D-gulofuranosyl thioglycosides and glycosyl sulfoxides in the synthesis of α-D-galactofuranosidic bonds, which are present in a range of bacterial and fungal glycoconjugates. This two-step method involves a stereosele

Full text of DOI:10.1021/jo061713o

2,3-Anhydrosugars in Glycoside Bond Synthesis. Application to
r-D-Galactofuranosides
Yu Bai and Todd L. Lowary*
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The UniVersity of
Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, Alberta T6G 2G2, Canada
tlowary@ualberta.ca
ReceiVed August 17, 2006
We report here the use of 2,3-anhydro-D-gulofuranosyl thioglycosides and glycosyl sulfoxides in the
synthesis of R-D-galactofuranosidic bonds, which are present in a range of bacterial and fungal
glycoconjugates. This two-step method involves a stereoselective glycosylation in which a 2,3-anhydro-
R-D-gulofuranoside is obtained either as the sole or as the major product, followed by a regioselective
opening of the epoxide ring using lithium benzylate in the presence of (-)-sparteine. In exploring the
scope of the method, donors protected at O5 and O6 with an isopropylidene acetal, benzyl ethers, or
benzoate esters were studied. Overall, the glycosyl sulfoxides provided the products in slightly higher
yields and selectivity, with the best results being obtained with benzylated and benzoylated substrates. In
the epoxide ring-opening reactions, the acetal- and ether-protected donors afforded poor to modest
regioselectivity, whereas the benzoylated products gave good yields of the desired R-D-galactofuranosides.
The benzoyl-protected species are, therefore, the donors of choice for these reactions. The utility of the
approach was demonstrated through the synthesis of three R-D-galactofuranosyl-containing oligosaccha-
rides.
Introduction
In previous reports, we have described the use of 2,3-
anhydrosugar thioglycosides and glycosyl sulfoxides in the
stereocontrolled synthesis of oligosaccharides containing ara-
binofuranosyl residues.1-3 Glycosylating agents 1 and 2 (Figure
1), upon coupling with a range of different alcohols, provide
glycosides with the 2,3-anhydro-â-D-lyxo stereochemistry (e.g.,
3), which in turn can be converted to â-arabinofuranosides (e.g.,
4) by reaction with lithium benzylate (BnOLi) in the presence
of (-)-sparteine followed by deprotection.1,2 Analogously,
donors 5 and 6 give R-arabinofuranosides (e.g., 8) via 2,3-
anhydro-R-D-ribofuranosides (e.g., 7); however, in these cases,
the additive is not necessary in the epoxide-opening step.3 The
method has also been applied to the synthesis of nucleosides.4
FIGURE 1. 2,3-Anhydro-pentofuranose derivatives in the synthesis
of arabinofuranosides.
We subsequently demonstrated5 that for the sulfoxide donors
the high glycosylation selectivity was due to the formation of
a single glycosyl triflate intermediate that reacted with the
alcohol via an SN2-like displacement.6 The origin of the
(1) Gadikota, R. R.; Callam, C. S.; Lowary, T. L. Org. Lett. 2001, 3,
607-610.
(2) Gadikota, R. R.; Callam, C. S.; Wagner, T.; Del Fraino, B.; Lowary,
T. L. J. Am. Chem. Soc. 2003, 125, 4155-4165.
(3) Cociorva, O. M.; Lowary, T. L. Tetrahedron 2004, 60, 1481-1489.
(4) Callam, C. S.; Gadikota, R. R.; Lowary, T. L. Synlett 2003, 1271-
1274.
(5) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am.
Chem. Soc. 2003, 125, 13112-13119.
(6) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386-5389.
10.1021/jo061713o CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2006
9658
J. Org. Chem. 2006, 71, 9658-9671

2,3-Anhydrosugars in Glycoside Bond Synthesis
CHART 1
CHART 2
stereoselectivity with the thioglycosides remains unclear. With
regard to the epoxide-opening reactions, the high selectivity for
C2 attack of the nucleophile in the 2,3-anhydro-R-D-ribofura-
nosides (7) is presumably due to steric effects, the hydroxy-
methyl substituent disfavoring attack at C3.7 The preference for
nucleophiles to attack C3 in 2,3-anhydro-â-D-lyxofuranosides
(3) in the presence of (-)-sparteine is unrelated to the chirality
of the additive,2 but the factors that underlie the regioselectivity
of this reaction have not been clarified.
of the glycan (10), liberated upon reductive â-elimination of
glycoproteins in the cellulosomes of Bacteriodies cellulosolVens.9e
In this synthesis, a fully benzylated trichloroacetimidiate donor
was used to install the R-D-galactofuranosyl residue. In addition,
two homologous immunomodulatory glycolipids (11), both of
which contain a single R-D-galactofuranosyl residue, have been
synthesized using carboxybenzyl glycoside donors.14 Another
recent study15 reported the application of the Ogawa-Ito
variant16 of the intramolecular aglycon delivery method to the
synthesis of an R-D-fucofuranosyl-containing disaccharide (12)
related to an antigenic polysaccharide from Eubacterium sabur-
reum strain T19.17
Our previous success with this class of glycosylating agent
has prompted us to extend our studies to the synthesis of
glycoconjugates containing other 1,2-cis-linked furanose resi-
dues. We report here the application of the 2,3-anhydrosugar
methodology to the synthesis of R-D-galactofuranosides (9, Chart
1). Although â-D-galactofuranosides are more widespread in
nature,8 a number of bacterial and fungal glycoconjugates
contain R-D-galactofuranosyl9 or R-D-fucofuranosyl (6-deoxy-
D-galactofuranosyl)10 residues, and the stereoselective synthesis
of these glycosidic linkages has been problematic.11 Indeed, only
very recently have studies focused on the stereocontrolled
preparation of R-D-galactofuranosyl-containing glycoconjugates
been reported.12-14 These investigations led13 to the synthesis
Results and Discussion
Synthesis of Glycosyl Donors. The preparation of R-D-
galactofuranosides via our 2,3-anhydrosugar methodology re-
quires the synthesis of donors with the 2,3-anhydro-D-
gulofuranoside stereochemistry, and thus, we targeted thioglyco-
sides 13-15 (Chart 2) and glycosyl sulfoxides 16-18 for
synthesis. In addition to studying the potential of these reagents
in glycoside synthesis, we also wanted to evaluate three different
classes of protecting groups on O5 and O6 to determine what,
if any, effect the protecting group had on the stereoselectivity
of the glycosylation. In addition, previous studies18 suggested
that the nature of protecting groups at these positions might
also influence the regioselectivity of the epoxide-opening
reaction.
(7) Williams, N. R. AdV. Carbohydr. Chem. Biochem. 1970, 25, 109-
179.
(8) (a) de Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547-
552. (b) Houseknecht, J. B.; Lowary, T. L. Curr. Opin. Chem. Biol. 2001,
5, 677-682.
(9) Representative examples of R-galactofuranosyl-containing polysac-
charides: (a) Hoffman, J.; Lindberg, B.; Glowacka, M.; Derylo, M.;
Lorkiewicz, Z. Eur. J. Biochem. 1980, 105, 103-107. (b) Jansson, P.-E.;
Lindberg, B. Carbohydr. Res. 1980, 82, 97-102. (c) Richards, J. C.; Perry,
M. B.; Kniskern, P. J. Can. J. Chem. 1989, 67, 1038-1050. (d) Gerwig,
G. J.; Kamerling, J. P.; Vliegenthart, J. F. G.; Morag, E.; Lamed, R.; Bayer,
E. A. Eur. J. Biochem. 1992, 205, 799-808. (e) Gerwig, G. J.; Kamerling,
J. P.; Vliegenthart, J. F. G.; Morag, E.; Lamed, R.; Bayer, E. A. J. Biol.
Chem. 1993, 268, 26956-26960. (f) Takayanagi, T.; Kimura, A.; Chiba,
S.; Ajisaka, K. Carbohydr. Res. 1994, 256, 149-158. (g) Parra, E.; Jime´nez-
Barbero, J.; Bernabe´, M.; Leal, J. A.; Prieto, A.; Go´mez-Miranda, B.
Carbohydr. Res. 1994, 251, 315-325. (h) Linnerborg, M.; Wollin, R.;
Wildmalm, G. Eur. J. Biochem. 1997, 246, 565-573. (i) Ahrazem, O.;
Prieto, A.; Leal, J. A.; Jime´nez-Barbero, J.; Bernabe´, M. Carbohydr. Res.
2002, 337, 1503-1506. (j) Ahrazem, O.; Prieto, A.; San-Blas, G.; Leal, J.
A.; Jime´nez-Barbero, J.; Bernabe´, M. Glycobiology 2003, 13, 743-747.
(k) San-Blas, G.; Prieto, A.; Bernabe´, M.; Ahrazem, O.; Moreno, B.; Leal,
J. A. Med. Mycol. 2005, 43, 153-159.
The synthesis of 13-18 started from D-galactose. A number
of methods have been reported for converting galactose from
(12) Gola, G.; Libenson, P.; Gandolfi-Donad´ıo, L.; Gallo-Rodriguez, C.
ARKIVOC 2005, XII, 234-242.
(10) Representative examples of R-D-fucofuranosyl-containing polysac-
charides: (a) Hoffman, J.; Lindberg, B.; Hofstad, T.; Lygre, H. Carbohydr.
Res. 1977, 58, 439-442. (b) Hanniffy, O. M.; Shashkov, A. S.; Moran, A.
P.; Prendergast, M. M.; Senchenkova, S. N.; Knirel, Y. A.; Savage, A. V.
Carbohydr. Res. 1999, 319, 124-132. (c) Zdorovenko, E. L.; Ovod, V.
V.; Zatonsky, G. V.; Shaskov, A. S.; Kocharova, N. A.; Knirel, Y. A.
Carbohydr. Res. 2001, 330, 505-510.
(11) (a) Osumi, K.; Enomoto, M.; Sugimura, H. Carbohydr. Lett. 1996,
2, 35-38. (b) Gelin, M.; Ferrie`res, V.; Plusquellec, D. Carbohydr. Lett.
1996, 2, 381-388. (c) Gelin, M.; Ferrie`res, V.; Plusquellec, D. Eur. J. Org.
Chem. 2000, 1423-1431.
(13) Gandolfi-Donad´ıo, L.; Gola, G.; de Lederkremer, R. M.; Gallo-
Rodriguez, C. Carbohydr. Res. 2006, 341, 2487-2497.
(14) Lee, Y. J.; Lee, B.-Y.; Jeon, H. B.; Kim, K. S. Org. Lett. 2006, 8,
3971-3974.
(15) Gelin, M.; Ferrie`res, V.; Lefeuvre, M.; Plusquellec, D. Eur. J. Org.
Chem. 2003, 1285-1293.
(16) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765-
1767.
(17) Sato, N.; Nakazawa, F.; Sato, M.; Hoshino, E.; Ito, T. Carbohydr.
Res. 1993, 245, 105-111.
(18) Callam, C. S.; Lowary, T. L. Unpublished results.
J. Org. Chem, Vol. 71, No. 26, 2006 9659

Bai and Lowary
SCHEME 1a
a Conditions: (a) 1,3-dibromo-5,5-dimethylhydantoin; (b) Ac2O, pyridine, rt, 61% over two steps; (c) p-TolSH, BF3‚OEt2, CH2Cl2, 0 °C, 76%; (d) NaOCH3,
CH3OH, rt, 88%; (e) (CH3)2C(OCH3)2, acetone, p-TsOH; (f) DIAD, Ph3P, THF, 0 °C, 81% from 23; (g) m-CPBA, CH2Cl2, -78 °C f rt, 84%.
the thermodynamically more stable pyranose form to the higher
energy furanose form, including Fischer glycosylation,19 high-
temperature acylation20 or anomeric alkylation,12 reduction of
galactonolactones,21 and the cyclization of dithioacetals22 or
open-chain S,O-acetals23 with mercuric salts. Many of these
approaches have limitations such as contamination with pyranose
forms, modest yields, or the use of expensive or toxic reagents.
The cyclization of dithioacetals in the presence of an alcohol
and iodine has also been reported.24 Advantages of this method
include a starting material that can be readily prepared in
multigram scale (albeit under malodorous conditions), inexpen-
sive reagents, and a lack of contamination by pyranose forms.
In the paper describing this chemistry, it was applied to
arabinose-, glucose-, and mannose-derived dithioacetals but not
to those obtained from galactose. To the best of our knowledge,
this method has not since been applied to the preparation of
galactofuranose derivatives; however, a recent paper reports an
analogous cyclization using 1,3-dibromo-5,5-dimethylhydantoin
and we therefore used this method.25
Thus, D-galactose (19, Scheme 1) was converted into its
diethyldithioacetal derivative, 20, upon treatment with HCl and
ethanethiol, as previously reported.26 Reaction of 20 with 1,3-
dibromo-5,5-dimethylhydantoin and methanol followed by
acetylation in acetic anhydride and pyridine gave a 35:65 R:â
mixture of methyl galactofuranosides, 21, in 61% yield over
two steps. Conversion of 21 into the corresponding p-tolyl
thioglycoside was achieved in 76% yield under the usual
conditions (boron trifluoride etherate and thiocresol),27 which
afforded 22 as a 1:9 R:â mixture (determined by integration of
NMR signals, 3JH1,H2 of major product ) 2.5 Hz). Deacetylation
of 22 with sodium methoxide in methanol afforded separable
thioglycosides 23 and 24 in a 10:1 ratio (based on isolated
yields) in an 88% combined overall yield from 22. The major
compound, 23, was taken forward, and installation of an isopro-
pylidene ketal at O5 and O6 proceeded without incident. The
product of this reaction, 25, was not characterized but instead
was directly treated with diisopropylazodicarboxylate (DIAD)
and triphenylphosphine. This sequence afforded 13 in 81% yield
from 23; none of the epoxide with the isomeric stereochemistry
was isolated. Oxidation28 of 13 with m-CPBA in dichlorometh-
ane afforded an 84% yield of the expected glycosyl sulfoxide
donor 16 as a 5.5:1 mixture of diastereomers. The stereochem-
istry at sulfur in these glycosyl sulfoxides was not established.
The presence of the oxirane ring in 13 and the diastereomers
of 16 was clearly demonstrated by the marked upfield shift (∼20
ppm) of the signals for C2 and C3 in the 13C NMR spectrum,
which appeared between 54.5 and 56.8 ppm. By analogy with
the stereochemically related arabinofuranose series,2,29 we
expected that epoxide formation would proceed to give the
expected product. However, it was impossible to determine the
orientation of the epoxide ring from the 1H and 13C NMR data
for these compounds. Fortunately, thioglycoside 13 is crystalline,
and a single-crystal X-ray diffraction study unambiguously
showed that the epoxide moiety is trans to the tolyl moiety and
cis to the C5/C6 side chain.30
With donors 13 and 16 in hand, we turned our attention to
the preparation of the other donors with the different side-chain-
protecting groups, a task we assumed could be done straight-
forwardly via acidic removal of the isopropylidene group in 13
and subsequent installation of benzyl- or benzoyl-protecting
groups and oxidation at sulfur. However, all attempts to remove
the 5,6-O-isopropylidene acetal in 13 failed, despite the evalu-
ation of a number of different conditions (80% aqueous HOAc,
20% aqueous HOAc, and p-TsOH/H2O). TLC monitoring of
these reactions showed the formation of one major spot, different
from 13. NMR analysis of the isolated material demonstrated
that the epoxide was no longer intact and that the thiotolyl group
had migrated to C2 (four methine carbon signals at 54.2-61.0
ppm). In addition, four signals were present in the anomeric
(19) Arasappan, A.; Fraser-Reid, B. Tetrahedron Lett. 1995, 36, 7967-
7070.
(20) D’Accorso, N. B.; Thiel, I. M. E.; Schu¨ller, M. Carbohydr. Res.
1983, 124, 177-184.
(21) Kohn, P.; Samaritano, R. H.; Lerner, L. M. J. Am. Chem. Soc. 1965,
87, 5475-5480.
1
region of the H NMR spectrum (4.6-6.0 ppm). On the basis
(22) Green, J. W.; Pacsu, E. J. Am. Chem. Soc. 1938, 60, 2056-2057.
(23) McAuliffe, J. C.; Hindsgaul, O. J. Org. Chem. 1997, 62, 1234-
1239.
of these data, we propose that this compound is a mixture of
the four cyclic forms of 2-deoxy-2-thiotolyl-D-idose (26, Figure
(24) Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R. Tetrahedron
Lett. 1986, 27, 3827-3830.
(25) Madhusudan, S. K.; Misra, A. K. Carbohydr. Res. 2005, 340, 497-
(28) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem.
Soc. 1989, 111, 6881-6882.
502.
(26) Norris, P.; Horton, D. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 35-52.
(27) Ferrier, R. J.; Furneaux, R. H. Methods Carbohydr. Chem. 1980, 8,
251-253.
(29) Martin, M. G.; Ganem, B.; Rasmussen, J. R. Carbohydr. Res. 1983,
123, 332-334.
(30) Bai, Y.; Lowary, T. L. Acta Crystallogr., Sect. E 2004, 60, o2201-
o2203.
9660 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
FIGURE 2. Formation of 2-deoxy-2-thiotolyl-D-idose upon attempted hydrolysis of the isopropylidene acetal in 13. In the proposed reaction
pathway, the loss of the isopropylidene acetal has arbitrarily been shown to precede migration.
SCHEME 2a
a Conditions: (a) trimethylorthoacetate, p-TsOH, rt; (b) DIAD, Ph3P, 0 °C f rt; (c) HCl wash, rt; (d) NaOCH3, CH3OH, rt, 72% from 23; (e) BnBr, NaH,
DMF, 0 °C f rt, 93%; (f) BzCl, pyridine, 0 °C f rt, 90%; (g) m-CPBA, CH2Cl2, -78 °C f rt, 87%; (h) m-CPBA, CH2Cl2, -78 °C f rt, 86%.
2), which presumably is formed by protonation of the epoxide
in 13 to give 27 and subsequent migration of the thiotolyl group
to form a sulfonium ion species (28) that is in turn hydrolyzed.
Analogous migration products have previously been identified
as byproducts in glycosylation reactions of 2,3-anhydrosugar
thioglycosides.1,2 Interestingly, the equilibrium mixture of 26
exists31 predominantly in the furanose form (71:29 furanose:
pyranose), in contrast to the parent sugar D-idose, which adopts
a ∼25:75 furanose:pyranose mixture.32 These differences are
presumably due to unfavorable steric interactions between the
thiotolyl moiety at C2 and O4 in the pyranose form33 and the
orientation of this large group on the top face of the ring in the
furanose forms, which is trans to the other bulky substituent,
the C5/C6 side chain.
on O5 and O6. We reasoned that as an orthoester is more acid
labile than an isopropylidene acetal, that very mild cleavage
conditions could be used to liberate the diol following the
Mitsunobu reaction thus leaving the epoxide intact. This
approach was successful, as outlined in Scheme 2; however,
the acid-sensitive nature of the orthoester required the initial
stages of the sequence to be carried out without purification of
intermediate products. Thus, reaction of 23 with trimethyl-
orthoacetate and p-toluenesulfonic acid led to the formation of
two new products that ran faster on TLC, which we assumed
were the diastereomeric orthoesters 29. Following neutralization
of the solution with triethylamine, DIAD and triphenylphosphine
were added, leading to the formation of a new spot on TLC,
presumably epoxide 30. The solution was concentrated, diluted
with ethyl acetate, and then washed in a separatory funnel with
dilute aqueous HCl (0.3%), providing two new spots on TLC,
which we assign as a mixture of acetate esters 31 and 32.
Treatment of the mixture of 31 and 32 with sodium methoxide
provided a single product, which was purified and shown to be
Faced with this difficulty, we chose an alternate route to the
benzyl- and benzoyl-protected donors 14, 15, 17, and 18. Key
to this new route was the use of an orthoester-protecting group
(31) The ratio of cyclic forms was calculated by the integration of
anomeric proton signals in the 1H NMR spectrum, with the peak assignments
being made by 1H-1H COSY and HMQC experiments. Assignment of
anomeric carbon signals in the 13C NMR spectrum was done by comparison
with published data for D-idose (Bock, K.; Pedersen, C. AdV. Carbohydr.
Chem. Biochem. 1983, 41, 27-66). Anomeric proton resonances: 5.51 ppm
(3J1,2 ) 4.8 Hz, correlated to 13C signal at 97.7 ppm; â-furanose), 5.25
ppm (3J1,2 ) 2.6 Hz, correlation to 13C signal at 94.1 ppm; R-pyranose),
5.17 ppm (3J1,2 ) 2.1 Hz, correlated to 13C signal at 103.5 ppm; R-furanose),
5.08 ppm (3J1,2 ) 4.1 Hz, correlation to 13C signal at 95.3 ppm; â-pyranose).
(32) Angyal, S. J. AdV. Carbohydr. Chem. Biochem. 1984, 42, 15-68.
(33) If the pyranose ring were to flip into the other chair conformation,
the C5 hydroxymethyl group would be axial, which is energetically
disfavored although not impossible; alternative ring forms are also possible.
3
3
However, in the R-pyranose form, the JH1,H2 and JH2,H3 values are 2.6
and 3.2 Hz, respectively, which suggests that this ring adopts predominantly
3
the 4C1 chair conformer. For the â-pyranose form, JH1,H2 ) 4.1 Hz and
3JH2,H3 ) 6.2 Hz, suggesting that other ring conformers are present.
Nevertheless, we feel the ratio of cyclic forms can be rationalized by these
simple steric arguments.
J. Org. Chem, Vol. 71, No. 26, 2006 9661

Bai and Lowary
CHART 3
glycosylation products, we explored the reaction of 13-18 with
a range of alcohols (38-45).35 This panel of acceptors included
primary, secondary, and tertiary simple alcohols, as well as
primary and secondary carbohydrate acceptors (Chart 4).
Activation of thioglycosides 13-15 was achieved by the
treatment of a solution of the donor and acceptor in di-
chloromethane at -40 °C with N-iodosuccinimide and silver
trifluoromethanesulfonate (NIS/AgOTf).36 As a comparison with
the NIS/AgOTf method, we also explored the activation of
thioglycoside 15 using 1-benzenesulfinylpiperidine and tri-
fluoromethanesulfonic anhydride (BSP/Tf2O) in dichloro-
methane.37 With sulfoxide donors 16-18, we employed Tf2O
activation38 in dichloromethane using the protocol developed
by Crich and Sun39 and modified by our group for 2,3-
anhydrosugar glycosyl sulfoxides.2 Under these conditions, the
sulfoxide was first treated with Tf2O in the presence of 2,6-di-
tert-butyl-4-methylpyridine (DTBMP), and then the solution was
stirred at -78 °C for 10 min. The solution was then warmed to
-40 °C and stirred for another 20 min prior to the addition of
the alcohol.
TABLE 1. Selected NMR Parameters in 34-37a
compound
34
35
36
37
C1 stereochemistry
H1/Oep relationship
R
â
cis
R
â
trans
5.08
101.6
163
trans
5.18
101.6
167
cis
δ
H1 (ppm)
C1 (ppm)
5.09
101.3
174
5.16
101.8
174
δ
1JC1,H1b (Hz)
a Spectra measured in CDCl3. b Measured using 1H-coupled HMQC
experiments.
The results of these glycosylations (Tables 2 and 3) clearly
indicate that donors 13-18 do efficiently glycosylate a range
of alcohols with a high degree of stereocontrol. Primary,
secondary, and tertiary alcohols are readily glycosylated in high
yields. Primary and secondary carbohydrate acceptors also work
well. In all of these examples, the major or exclusive product
is the R-glycoside, in which the newly formed glycosidic linkage
is cis to the epoxide moiety; the stereochemistry of all products
diol 33. The conversion of 23 into 33 proceeded in excellent
overall yield, 72%. With 33 in hand, its conversion to the benzyl-
protected thioglycoside under standard conditions was straight-
forward, affording the product 14 in 93% yield. Similarly,
benzoylation of 33 afforded a high (90%) yield of 15. Oxidation
of 14 and 15 to the corresponding glycosyl sulfoxides 17 and
18 proceeded uneventfully in 87% and 86% yields, respectively.
As in the synthesis of 16 from 13 (Scheme 1), sulfoxides 17
and 18 were obtained as a mixture of diastereomers on sulfur
(2:1 for 17 and 1.7:1 for 18), but the stereochemistry was not
determined.
Distinguishing Anomeric Stereochemistry in 2,3-Anhydro-
gulofuranosides. Before investigating glycosylation reactions
with 13-18, it was necessary to establish a reliable method for
easily distinguishing 2,3-anhydro-R-D-gulofuranosides, the de-
sired products of these reactions, from their â-glycoside
counterparts. Previous work34 from our laboratory demonstrated
that the one-bond coupling constant between C1 and H1 in 2,3-
anhydro-O-pentofuranosides (e.g., 3 and 7, Figure 1) is diag-
nostic of the stereochemistry at the anomeric center. For
1
was determined by measurement of the JC1,H1 as described
above.
On the basis of the yields and R:â ratios shown in Tables 2
and 3, some trends can be identified. First, in general, the yields
and R-selectivity of the glycosylation reactions decrease with
increasing steric hindrance on the acceptor alcohol. For example,
tertiary alcohols (Table 2, entry 8, and Table 3, entry 3) and
carbohydrate secondary alcohol acceptors (Table 2, entry 10,
and Table 3, entry 5) give somewhat lower yields and poorer
selectivities compared to other acceptors. However, the R:â
ratios are better than 4:1 in most cases. The worst selectivity
(3:1 R:â) is observed in the reactions of relatively hindered
alcohols 40 and 42 with thioglycoside 14 (Table 2, entries 8
and 10). Second, a comparison of the glycosylation reactions
with thioglycosides 13-15 (Table 2) versus sulfoxides 16-18
(Table 3) reveals that these sulfoxide donors generally provide
better R-selectivities, regardless of the structure of the acceptor.
Third, the thioglycoside glycosylations appear to be only slightly
affected by switching the promoter from NIS/AgOTf to BSP/
Tf2O (Table 2, entries 14, 15, 18, and 19). Both methods lead
to glycoside formation although the yields and selectivities are
marginally lower with BSP/Tf2O activation; the reactions are
1
glycosides in which H1 is trans to the epoxide moiety, JC1,H1
) 163-168 Hz; when this hydrogen is cis to the oxirane ring,
1JC1,H1 ) 171-174 Hz. However, because the results of our
previous study were based on glycosides with the lyxo and ribo
stereochemistry, model studies were necessary to verify the
suitability of this parameter for differentiating 2,3-anhydro-D-
gulofuranosides. Therefore, two R/â pairs of 2,3-anhydro-D-
gulofuranosides, 34-37 (Chart 3), were synthesized by unam-
1
biguous routes (see Supporting Information), and the JC1,H1
(35) Alcohols 38-40 are commercially available. All others were
prepared by reported methods. 41: ref 34. 42: ref 2. 43: Pozsgay, V.;
Brisson, J. R.; Jennings, H. J. Can. J. Chem. 1987, 65, 2764-2769. 44:
Beignet, J.; Tiernan, J.; Woo, C. H.; Kariuki, B. M.; Cox, L. R. J. Org.
Chem. 2004, 69, 6341-6356. 45: Garegg, P. J.; Hultberg, H.; Wallin, S.
Carbohydr. Res. 1982, 108, 97-101.
values were measured (Table 1). These data demonstrate that
the trends we identified earlier can be applied to products
obtained from glycosylations of 13-18. Also presented in Table
1 are data underscoring that the chemical shifts of the anomeric
hydrogen or anomeric carbon resonances are not reliable
predictors of stereochemistry in 2,3-anhydrosugar glycosides,
as was reported in our earlier study.34
(36) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett.
1990, 31, 4313-4316.
(37) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(38) (a) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.
(b) Gildersleeve, J.; Pascal, R. A., Jr.; Kahne, D. J. Am. Chem. Soc. 1998,
120, 5961-5969. (c) Gildersleeve, J.; Smith, A.; Sakurai, K.; Raghavan,
S.; Kahne, D. J. Am. Chem. Soc. 1999, 121, 6176-6182.
(39) (a) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199. (b) Crich,
D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507.
Glycosylation Reactions. With the donors in hand and an
NMR method in place for distinguishing between the two
(34) Callam, C. S.; Gadikota, R. R.; Lowary, T. L. J. Org. Chem. 2001,
66, 4549-4558.
9662 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
CHART 4
TABLE 2. Glycosylation of Alcohols with Thioglycoside Donors
TABLE 3. Glycosylation of Alcohols with Glycosyl Sulfoxide
13-15a
Donors 16-18a
entry donor
activator
acceptor product yield (%) R:â ratiob
entry
donor
acceptor
product
yield (%)
R:â ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
13
13
13
13
13
14
14
14
14
14
15
15
15
15
15
15
15
15
15
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
NIS/AgOTf
BSP/Tf2O
38
39
40
41
42
38
39
40
41
42
38
39
40
41
42
43
45
41
42
34
46
47
36
48
49
50
51
52
53
54
55
56
57
58
59
61
57
58
82
83
82
79c
56d
87
80
80
81
75
81
79
80
82
75
78
72
78
74
R only
R only
R only
5:1
10:1
9:1
5:1
3:1
7:1
3:1
R only
R only
9:1
10:1
R only
8:1
8:1
6:1
7:1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
16
16
16
16
16
17
17
17
17
17
18
18
18
18
18
18
18
38
39
40
41
42
38
39
40
41
42
38
39
40
41
42
44
45
34
46
47
36
48
49
50
51
52
53
54
55
56
57
58
60
61
78
79
71
71
73
82
81
76
79
72
87
81
78
82
76
75
72
R only
R only
4:1
6:1
5:1
R only
R only
10:1
R only
R only
R only
R only
R only
R only
R only
14:1
R only
a See Experimental Section for activation procedure. b Ratio determined
by weights of isolated pure compounds.
BSP/Tf2O
a See Experimental Section for activation procedure. b Ratio determined
by weights of isolated pure compounds. c 15% migration product was
isolated (see text). d 19% migration product was isolated (see text).
spectrum. The formation of these side products is attributed to
the presence of trifluoromethanesulfonic acid generated as the
reaction proceeds, which induces the rearrangement process,
presumably via a pathway similar to that shown in Figure 2.
Epoxide-Opening Reactions. Having demonstrated that the
donors 13-18 can be used in the stereocontrolled synthesis of
2,3-anhydro-R-D-gulofuranosides (e.g., 34, Table 4), we next
sought to explore the regioselective opening of the epoxide ring
in these molecules. Taking into account only steric consider-
ations, attack of the nucleophile at either C2 or C3 should be
equally likely, given that the top face of the furanose ring in
2,3-anhydro-D-gulofuranosides has no substituents that could
bias the approach of the nucleophile. However, previous work
on the syntheses of the stereochemically analogous â-D-
arabinofuranosides from the corresponding epoxide precursor
(3 f 4, Figure 1)2 indicated that the combined use of BnOLi
and (-)-sparteine in benzyl alcohol at 70 °C afforded good to
also slower compared to the NIS/AgOTf-promoted glycosyla-
tions (45 min vs 12 h). Finally, the protecting groups on O5
and O6 influence the reaction outcome. Glycosylation with both
the benzyl- and benzoyl-protected donors (14, 15, 17, and 18)
gives somewhat higher yields and better R-selectivities than the
isopropylidene-protected donors 13 and 16, especially when
carbohydrate acceptors are used (Table 2, entries 5, 10, and 15;
Table 3, entries 5, 10, and 15). In some reactions involving
thioglycoside 13, significant amounts of 2-deoxy-2-thiotolyl-
R-D-idofuranosides (Chart 5) were produced in addition to the
desired 2,3-anhydro-D-gulofuranosyl glycosides (Table 2, entries
4 and 5). These compounds were isolated in a mixture with
other reaction components (e.g., unreacted acceptor), and their
quantitation was done by integration of signals in the 1H NMR
J. Org. Chem, Vol. 71, No. 26, 2006 9663

Bai and Lowary
TABLE 4. Opening of Epoxides 34, 49, and 54 with BnOLia
products
(D-Galf, D-Idof)
yield
(%)
ratio
entry
substrate
additive
(Galf:Idof)b
1
2
3
4
5
6
7
34
34
49
49
54
54
54
-
64, 65
64, 65
66, 67
66, 67
68, 69
68, 69
68, 69
75
75
84
85
76
78
82
1:1.8b
1:1.5b
1:3.2c
1:2.9c
3.3:1b
4.8:1b
1.8:1b
(-)-sparteine
-
(-)-sparteine
-
(-)-sparteine
TMPDA
a See Experimental Section for reaction conditions. b Determined by weights of isolated pure compounds. c Determined by integration of anomeric hydrogen
1
resonances in the H NMR spectrum obtained on the mixture of 66 and 67, which were not separable by chromatography.
CHART 5
CHART 6
excellent selectivity for attack of the nucleophile at C3. In the
case of the 2,3-anhydro-R-D-gulofuranoside ring system, attack
of the nucleophile at C3 provides the desired product with the
D-galactofuranose (D-Galf) stereochemistry, while reaction at
C2 yields products with the D-idofuranose (D-Idof) stereochem-
istry.
substrate 54 was used, the regioselectivity of a nucleophilic
attack increased, and moreover, attack at C3 was favored thus
leading to a preponderance of the D-Galf-configured product
(Table 4, entries 5 and 6). In the absence of (-)-sparteine, a
3.3:1 D-Galf/D-Idof mixture was produced, and this ratio
increased to nearly 5:1 in the presence of the additive. The use
of TMPDA as the additive provided results inferior to those
obtained with (-)-sparteine (Table 4, entry 7).
We evaluated three octyl glycosides (34, 49, and 54)
synthesized in the context of the glycosylation studies described
previously as model systems. Each of these three epoxides was
heated at 75 °C with 6.0 equiv of BnOLi in benzyl alcohol,
either in the presence or absence of 1.2 equiv of (-)-sparteine;
N,N,N′,N′-tetramethyl-1,3-propanediamine (TMPDA) was also
studied as an additive. The yields and D-Galf:D-Idof ratios for
these reactions are presented in Table 4. These compounds could
readily be differentiated from their 1H NMR spectra. The
anomeric hydrogen of those compounds with the D-Galf
The role that the O5- and O6-protecting group plays on this
process is striking. Clearly, for substrates containing protecting
groups that are stable under the reaction conditions (isoprop-
ylidene acetal, benzyl ethers), poor to modest regioselectivity
is observed, and nucleophilic attack at C2 is favored. In contrast,
for the system in which O5 and O6 are protected with base-
labile-protecting groups, the reaction is more regioselective, and
there is an “inversion” in the favored position of the attack. In
our previous studies on the synthesis of â-arabinofuranosides
by this approach, the substrates for the ring-opening reactions
(e.g., 3, Figure 1) either were protected at O5 with a benzoyl
group or were unprotected.2 We are unsure as to the origin of
these regioselectivity trends, but these results, combined with
those obtained in our earlier study, point to the possible
importance of a complex formed between the substrate, (-)-
sparteine, and the lithium ion. If the assumption is made that
the benzoate esters are cleaved rapidly in the initial stages of
the reaction, thus liberating the corresponding alkoxide, the
formation of a complex of the general type (70, Chart 6) can
be envisioned, which may, through a currently undetermined
mechanism, influence the site of nucleophilic attack. The
formation of related complexes has been proposed in the
sparteine-mediated enantioselective lithiation of meso epoxides
3
stereochemistry appeared as a doublet with a J1,2 of 3-5 Hz,
whereas this signal in the D-Idof-configured products appeared
as a singlet.40 These reactions proceeded efficiently, with
combined product yields ranging from 75-85%. However, the
regioselectivity of these reactions was variable and depended
upon the nature of the protecting group on O5 and O6. With
the isopropylidene-protected substrate, 34, the regioselectivity
was poor, and C2 attack was favored, leading to a slight
predominance of the D-Idof product (Table 4, entry 1). With
the benzyl-protected system, 49 (Table 4, entry 3), the reaction
was more regioselective, and again the D-Idof product was
favored. With both 34 and 49, the addition of (-)-sparteine had
little effect and, if anything, eroded the regiocontrol slightly.
In contrast to these two systems, when the benzoyl-protected
(40) Cyr, N.; Perlin, A. S. Can. J. Chem. 1979, 57, 2504-2511.
9664 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
CHART 7
SCHEME 3a
starting material. Opening of the epoxide with our standard
conditions afforded disaccharide 76 in 65% yield together with
13% of the regioisomeric product, which were separated.
Hydrogenation of the benzyl groups in 76 afforded a 94% yield
of the target 72.
Presented in Scheme 3B is the synthesis of disaccharide 73,
which also began from one of the products obtained in the
exploration of the scope of the methodology, 60. Reaction of
this disaccharide with LiOBn and (-)-sparteine afforded the
ring-opened product 77 in 55% yield along with the 18% of
the regioisomer with the D-Idof stereochemistry. Removal of
the benzyl groups by hydrogenation over Pd/C afforded 73 in
quantitative yield.
The synthesis of trisaccharide 74 was more involved and is
depicted in Scheme 4. The target has two R-D-galactofuranosyl
moieties linked (1f2), and, therefore, the glycosylation/ring-
opening sequence inherent in the 2,3-anhydrosugar methodology
makes this an attractive approach for the synthesis of compounds
containing this motif. Thus, disaccharide 61, obtained by
glycosylation of alcohol 45 with glycosyl sulfoxide 18 (Table
3, entry 17), was treated with LiOBn and (-)-sparteine to
provide the ring-opened product 78 in 69% yield, together with
5% of the regioisomeric product. The C5/C6 diol motif liberated
in the ring opening was protected as an isopropylidene acetal
giving an 89% yield of disaccharide 79.
a Conditions: (a) LiOBn, (-)-sparteine, BnOH, 75 °C, 65%; (b) H2, Pd/
C, CH3OH, rt, 94%; (c) LiOBn, (-)-sparteine, BnOH, 75 °C, 55%; (d) H2,
Pd/C, CH3OH, rt, quantitative.
by organolithium reagents.41 An alternate possibility is that a
complex of the type 71 is produced, which could lead to the
delivery of the nucleophile preferentially to C3. In the absence
of the additive, analogous complexes involving lithium ions and
additional alkoxide ligands are possible. Despite these postulates,
to date we have no evidence for the formation of species such
as 70 and 71 in these reactions, and studies exploring their
intermediacy, by both experimental and computational ap-
proaches, are ongoing. Among the questions to be addressed
are the origin of the regioselectivity and the erosion seen when
moving from the pentofuranose to the hexofuranose systems,
as well as the relatively poor performance of other diamine
ligands (e.g., TMPDA).
Application to the Synthesis of R-D-Galactofuranosyl-
Containing Oligosaccharides. To illustrate further the utility
of this methodology, we selected three small target molecules
for synthesis. These were a disaccharide fragment of the
lipopolysaccharide from Salmonella typhimurium 9029a (72,
Chart 7), the repeating unit of a cell wall polysaccharide from
Talaromyces flaVus9g (73), and a trisaccharide (74) structurally
related to an antigenic polysaccharide from Eubacterium sabur-
reum strain T19 (75).10b
Glycosylation of the C2′ hydroxyl group in 79 initially proved
problematic. We first explored the use of thioglycoside 15 for
this purpose, and given the hindered nature of the acceptor,
extended reaction times (>2 h) were required for reasonable
levels of conversion of the acceptor. Under these conditions,
only very small amounts of the desired product, 80, were
produced. The major products were hydrolyzed donor, unreacted
79 and trisaccharide 81, in which the isopropylidene acetal had
been cleaved. It appears that at the extended reaction times
necessary for the glycosylation to occur, the trifluoromethane-
sulfonic acid liberated over the course of the reaction leads to
cleavage of the isopropylidene-protecting group. This acetal
appears to be particularly susceptible to acid-promoted cleavage.
For example, while we could easily record the 1H NMR
spectrum of 80 in CDCl3, when we attempted to obtain the 13
C
NMR spectrum, we observed cleavage of the acetal over the
(longer) course of the experiment. This degradation presumably
arises from trace amounts of acid impurities present in com-
mercial preparations of CDCl3. Although we are unsure as to
why this acetal is so acid-labile, we believe it is related to the
highly hindered nature of the central galactofuranosyl residue
in 80. Faced with this problem, we glycosylated 79 with
sulfoxide 18, a reaction that proceeds under slightly basic
conditions. Although again extended reaction times were
necessary, we were successful in obtaining disaccharide 80 in
59% yield.
The synthesis of 72 is illustrated in Scheme 3A. Disaccharide
59, which could be obtained from the reaction of alcohol 43
(Chart 4) and 15 as outlined above (Table 2, entry 16), was the
(41) (a) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006,
1-22. (b) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin Trans. 1 1998, 2151-
2161.
J. Org. Chem, Vol. 71, No. 26, 2006 9665

Bai and Lowary
SCHEME 4a
a Conditions: (a) LiOBn, (-)-sparteine, BnOH, 75 °C, 69%; (b) (CH3)2C(OCH3)2, acetone, p-TsOH, rt, 89%; (c) 18, Tf2O, DTBMP, CH2Cl2, -78 °C f
rt, 59%; (d) LiOBn, (-)-sparteine, BnOH, 75 °C, 61%; (e) HOAc, H2O, 50 °C, 81%; (f) H2, Pd(OH)2/C, CH3OH, rt, quantitative.
Conversion of 80 into the target product proceeded straight-
forwardly by first epoxide ring opening under the usual
conditions, which provided triol 82 in 61% yield together with
13% of the regioisomeric product. Cleavage of the acetal with
aqueous acetic afforded 83, which was then hydrogenated over
Pearlman’s catalyst thus providing the product 74 in 81% overall
yield.
Experimental Section
Activation of Thioglycoside Donors by the AgOTf/NIS
Method. The donor (0.1 mmol), acceptor (1.2 equiv), and 4 Å
molecular sieves were dried overnight under vacuum in the presence
of P2O5. To this mixture was added CH2Cl2 (5 mL); the reaction
was cooled to -40 °C, and then NIS (1.2 equiv) and AgOTf (0.3
equiv) were successively added. After stirring for 20 min at -40
°C, the reaction solution was warmed to -25 °C. Once the color
of the reaction was changed to pink, it was cooled again to -40
°C. After another 30 min, the reaction mixture turned dark red and
was then neutralized by addition of triethylamine, diluted with
CH2Cl2, and filtered through Celite. The filtrate was washed with
saturated aq Na2S2O3 solution, dried (Na2SO4), and concentrated
to give a crude residue that was purified by chromatography to
yield the corresponding separable R (major) and â (minor)
glycosides.
Activation of Thioglycoside Donors by the BSP/Tf2O Method.
The donor (0.1 mmol), BSP (1.0 equiv), 2,4,6-tri-tert-butyl-
pyrimidine (2.0 equiv), and 4 Å molecular sieves were dried for 4
h under vacuum in the presence of P2O5. To this mixture was added
CH2Cl2 (5 mL), and the reaction mixture was cooled to -60 °C.
Tf2O (1.1 equiv) was added, and the mixture was allowed to stir
for 10 min, followed by the addition (via syringe) of a solution of
the vacuum-dried acceptor (1.1 equiv) in CH2Cl2 (1 mL). After 40
min, the reaction mixture was warmed to rt and was kept stirring
for 12 h. A saturated solution of NaHCO3 was then added, and the
resulting solution was filtered through Celite, dried, filtered, and
concentrated to yield a crude oil that was purified by chromatog-
raphy.
Conclusions
In summary, we have demonstrated that 2,3-anhydro-D-
gulofuranosyl thioglycosides and glycosyl sulfoxides 13-18 can
be used in highly stereoselective synthesis of 2,3-anhydro-R-
D-gulofuranosides. The nature of the protecting groups on O5
and O6 influences the stereoselectivity and yield of the
glycosylation reactions, with the best results being obtained
when benzoate esters are present at these positions. In addition,
glycosyl sulfoxides, in general, provide the product in better
yields and with higher stereoselectivity. We have also demon-
strated that the regioselective opening of the oxirane moiety in
the glycosylation products provides compounds with the R-D-
galactofuranoside stereochemistry by using a mixture of LiOBn
and (-)-sparteine. Here too, the protecting groups on O5 and
O6 play a critical role; only the benzoyl-protected substrates
yield the desired compounds with good selectivity. We attribute
this effect to the formation of a complex between the additive,
the nucleophile, and the alkoxide generated in situ upon cleavage
of the benzoate esters. The regioselectivities of these opening
reactions are not as high as those observed earlier in the
synthesis of â-arabinofuranosides,2 and we are currently inves-
tigating the origin of this loss in regioselectivity. Overall, the
best results were observed when benzoylated 2,3-anhydrosugar
donors were used in glycosylation reactions, and the corre-
sponding benzoylated substrates also gave the best results in
the epoxide-opening reactions. It appears, therefore, that acyl-
protected species are the donors of choice for these reactions.
Activation of Sulfoxide Donors by the Tf2O/DTBMP Method.
The donor (0.1 mmol), DTBMP (4.0 equiv), and 4 Å molecular
sieves were dried for 3 h under vacuum in the presence of P2O5.
To this mixture was added CH2Cl2 (5 mL), and the reaction mixture
was cooled to -78 °C. Tf2O (1.2 equiv) was added, and the mixture
was allowed to stir for 10 min. The solution was then warmed to
-40 °C and stirred for 20 min followed by the addition of the
acceptor alcohol (1.2 equiv). After 30-60 min, the reaction mixture
turned slight green; a saturated solution of NaHCO3 was then added,
and the solution was allowed to warm to rt. The resulting solution
was filtered through Celite, dried, filtered, and concentrated to yield
9666 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
a crude oil that was purified by chromatography to give the
corresponding separable R (major) and â (minor) glycosides.
General Procedure for Epoxide-Opening Reactions. To a
solution of benzyl alcohol (3.0 mL) was added lithium metal (6.0
mmol), and the solution was stirred at 65 °C until all the metal
dissolved. After cooling to rt, the mixture was added together with
the additive (1.2 mmol) via syringe to a solution of the epoxide
(1.0 mmol) dissolved in benzyl alcohol (0.5 mL). The resulting
mixture was subsequently warmed to 75 °C and stirred until the
reaction was complete. After cooling to rt, the solution was
neutralized with HOAc and diluted with EtOAc (10 mL). The
organic layer was washed with water, dried (Na2SO4), filtered, and
concentrated to give a crude residue that was purified by chroma-
tography. Those reactions done in the absence of an additive were
carried out in an analogous manner (additive ) (-)-sparteine or
TMPDA).
p-Tolyl 2,3-Anhydro-5,6-di-O-benzoyl-1-thio-â-D-gulofura-
noside (15). Benzoyl chloride (850 µL, 7.5 mmol) was added
dropwise to a solution of 33 (800 mg, 3.0 mmol) in pyridine (10
mL) at 0 °C. The reaction mixture was warmed to rt and stirred
for 12 h. The solution was diluted with CH2Cl2 (50 mL) and washed
with saturated aq NaHCO3 solution (3 × 40 mL). The organic layer
was dried (Na2SO4), filtered, concentrated, and purified by chro-
matography (6:1 hexanes/EtOAc) to yield 15 (1.28 g, 90%) as a
white semisolid foam. Rf 0.48 (3:1 hexanes/EtOAc); [R]D -90.8 (c
1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 8.10-8.07 (m, 2H,
Ar), 8.03-8.00 (m, 2H, Ar), 7.56-7.40 (m, 8H, Ar), 7.12-7.09
(m, 2H, Ar), 5.78 (dd, 1H, J ) 5.4, 5.0 Hz, H-5), 5.52 (s, 1H,
H-1), 4.73 (d, 2H, J ) 5.4 Hz, H-6 × 2), 4.33 (dd, 1H, J ) 5.0,
0.6 Hz, H-4), 3.90 (dd, 1H, J ) 2.8, 0.6 Hz, H-3), 3.89 (d, 1H, J
) 2.8 Hz, H-2), 2.32 (s, 3H, tolyl CH3); 13C NMR (125 MHz,
CDCl3, δC) 166.1 (CdO), 165.9 (CdO), 138.4 (Ar × 2), 133.4
(Ar × 2), 133.3 (Ar), 133.2 (Ar), 129.9 (Ar × 4), 129.8 (Ar), 129.7
(Ar × 2), 128.6 (Ar), 128.5 (Ar × 2), 128.4 (Ar × 2), 87.1 (C-1),
74.8 (C-4), 70.8 (C-5), 63.4 (C-6), 57.0 (C-2), 55.0 (C-3), 21.1
(tolyl CH3). HRMS (ESI): [M + Na] calcd for C27H24O6SNa,
499.1186; found, 499.1188.
2,3-Anhydro-5,6-O-isopropylidene-â-D-gulofuranosyl-p-tolyl-
(R/S)-sulfoxide (16a/16b). To a solution of 13 (620 mg, 2.0 mmol)
in CH2Cl2 (40 mL) at -78 °C was added m-CPBA (430 mg, 1.8
mmol). After stirring for 2 h, the reaction mixture was warmed to
rt and stirred for 30 min. The solution was washed with a saturated
aq solution of NaHCO3 (3 × 30 mL) and then water (3 × 30 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated
to yield a crude oil that was purified by chromatography (8:1
hexanes/EtOAc) to provide 16a (380 mg, 71%) and 16b (160 mg,
13%) as white semisolids. 16a: Rf 0.32 (1:1 hexanes/EtOAc); [R]D
+216.0 (c 1.3, CH2Cl2); 1H NMR (400 MHz, CDCl3, δH) 7.50 (d,
2H, J ) 8.5 Hz, Ar), 7.38 (d, 2H, J ) 8.5 Hz, Ar), 4.74 (s, 1H,
H-1), 4.43 (dd, 1H, J ) 6.5, 0.7 Hz, H-4), 4.27 (q, 1H, J ) 6.5 Hz,
H-5), 4.09 (dd, 1H, J ) 8.5, 6.5 Hz, H-6), 3.94 (d, 1H, J ) 2.9 Hz,
H-2), 3.93 (dd, 1H, J ) 8.5, 6.5 Hz, H-6), 3.84 (dd, 1H, J ) 2.9,
0.7 Hz, H-3), 2.44 (s, 3H, tolyl CH3), 1.48 (s, 3H, isopropylidene
CH3), 1.37 (s, 3H, isopropylidene CH3); 13C NMR (100 MHz,
CDCl3, δC) 142.1 (Ar), 136.4 (Ar), 130.3 (Ar × 2), 124.1 (Ar ×
2), 110.1 (isopropylidene C), 96.3 (C-1), 81.0 (C-4), 74.9 (C-5),
65.5 (C-6), 55.5 (C-3), 54.5 (C-2), 26.7 (isopropylidene CH3), 25.2
(isopropylidene CH3), 21.4 (tolyl CH3). HRMS (ESI): [M + Na]
calcd for C16H20O5SNa, 347.0924; found, 347.0926. 16b: Rf 0.20
(1:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, δH) 7.58-7.54
(m, 2H, Ar), 7.37-7.33 (m, 2H, Ar), 4.88 (s, 1H, H-1), 4.23-4.16
(m, 3H, H-4, H-5, H-2), 4.02 (dd, 1H, J ) 8.5, 6.5 Hz, H-6), 3.86
(dd, 1H, J ) 8.5, 5.5 Hz, H-6), 3.72 (dd, 1H, J ) 2.9, 0.7 Hz,
H-3), 2.44 (s, 3H, tolyl CH3), 1.45 (s, 3H, isopropylidene CH3),
1.34 (s, 3H, isopropylidene CH3); 13C NMR (100 MHz, CDCl3,
δC) 142.4 (Ar), 136.0 (Ar), 130.04 (Ar), 130.0 (Ar), 125.3 (Ar ×
2), 109.9 (isopropylidene C), 94.4 (C-1), 81.7 (C-4), 74.9 (C-5),
65.4 (C-6), 55.8 (C-2), 55.7 (C-3), 26.7 (isopropylidene CH3), 25.2
(isopropylidene CH3), 21.5 (tolyl CH3). HRMS (ESI): [M + Na]
calcd for C16H20O5SNa, 347.0924; found, 347.0922.
p-Tolyl 2,3-Anhydro-5,6-O-isopropylidene-1-thio-â-D-gulo-
furanoside (13). To a solution of 23 (2.15 g, 7.52 mmol) and 2,2-
dimethoxypropane (7.4 mL, 60.1 mmol) in acetone (50 mL) was
added p-toluenesulfonic acid (7 mg) at rt. The solution was allowed
to stir for 2 h and neutralized with Et3N. TLC showed a spot at Rf
) 0.40 (15:1 CH2Cl2/CH3OH). The mixture was concentrated, and
the resulting oil was dissolved in THF (40 mL) followed by the
addition of PPh3 (2.57 g, 9.78 mmol). DIAD (1.9 mL, 9.78 mmol)
was then added dropwise at 0 °C over 10 min. The reaction mixture
was allowed to warm to rt over 30 min. The resulting mixture was
concentrated, and Et2O (60 mL) was added to precipitate the
Ph3PdO, which was subsequently removed by filtration. The
organic layer was concentrated, and the residue was purified by
chromatography (6:1 hexanes/EtOAc) to yield 13 (1.87 g, 81% over
two steps) as a white solid. Rf 0.46 (4:1 hexanes/EtOAc); mp 76-
1
78 °C; [R]d -187.1 (c 1.5, CH2Cl2); H NMR (400 MHz, CDCl3,
δH) 7.45-7.41 (m, 2H, Ar), 7.13-7.11 (m, 2H, Ar), 5.48 (s, 1H,
H-1), 4.32 (ddd, 1H, J ) 6.3, 6.3, 6.3 Hz, H-5), 4.06 (dd, 1H, J )
8.6, 6.3 Hz, H-6), 4.01-3.97 (m, 2H, H-4, H-6), 3.88 (d, 1H, J )
2.9 Hz, H-2), 3.67 (dd, 1H, J ) 2.9, 0.5 Hz, H-3), 2.34 (s, 3H,
tolyl CH3), 1.47 (s, 3H, isopropylidene CH3), 1.37 (s, 3H,
isopropylidene CH3); 13C NMR (100 MHz, CDCl3, δC) 138.4 (Ar),
133.5 (Ar × 2), 129.9 (Ar), 128.6 (Ar × 2), 109.7 (isopropylidene
C), 87.3 (C-1), 77.0 (C-4), 74.6 (C-5), 65.6 (C-6), 56.8 (C-2), 54.9
(C-3), 26.6 (isopropylidene CH3), 21.1 (isopropylidene CH3), 21.1
(tolyl CH3). Anal. Calcd for C16H20O4S: C, 62.31; H, 6.54.
Found: C, 62.09; H, 6.68. HRMS (ESI): [M + Na] calcd for
C16H20O4SNa, 331.0975; found, 331.0976.
p-Tolyl 2,3-Anhydro-5,6-di-O-benzyl-1-thio-â-D-gulofurano-
side (14). To a solution of 33 (60 mg, 0.22 mmol) in DMF (1.5
mL) at 0 °C was added NaH (3 mg, 0.72 mmol, 60% dispersion in
oil), and the mixture was stirred for 5 min. Benzyl bromide (64
µL, 0.54 mmol) was added dropwise at 0 °C, and the mixture was
stirred for 6 h at rt. The reaction mixture was then quenched by
adding a few drops of CH3OH, diluted with CH2Cl2 (10 mL), and
washed with saturated aq NaHCO3 solution (3 × 10 mL) and water
(3 × 10 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated, and the resulting residue was purified by chroma-
tography (4:1 hexanes/EtOAc) to provide 14 (93 mg, 93%) as a
colorless oil. Rf 0.52 (4:1 hexanes/EtOAc); [R]D -127.6 (c 1.2,
CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 7.46-7.43 (m, 2H, Ar),
7.38-7.27 (m, 10H, Ar), 7.13 (d, 2H, J ) 7.9 Hz, Ar), 5.50 (s,
1H, H-1), 4.76 (d, 1H, J ) 11.8 Hz, PhCH2), 4.71 (d, 1H, J )
11.8 Hz, PhCH2), 4.59 (d, 1H, J ) 12.0 Hz, PhCH2), 4.54 (d, 1H,
J ) 12.0 Hz, PhCH2), 4.21 (d, 1H, J ) 6.3 Hz, H-4), 3.88-3.83
(m, 1H, H-5), 3.84 (d, 1H, J ) 2.9 Hz, H-2), 3.77-3.70 (m, 3H,
H-3, H-6 × 2), 2.38 (s, 3H, tolyl CH3); 13C NMR (125 MHz, CDCl3,
δC) 138.6 (Ar), 138.2 (Ar), 138.15 (Ar), 133.3 (Ar × 2), 129.8 (Ar
× 2), 129.1 (Ar), 128.4 (Ar × 2), 128.3 (Ar × 2), 127.8 (Ar × 2),
127.7 (Ar × 2), 127.6 (Ar), 127.5 (Ar), 87.0 (C-1), 77.7 (C-5),
77.5 (C-4), 73.5 (PhCH2), 73.1 (PhCH2), 70.8 (C-6), 56.9 (C-2),
55.4 (C-3), 21.1 (tolyl CH3). HRMS (ESI): [M + Na] calcd for
C27H28O4SNa, 471.1601; found, 471.1600.
2,3-Anhydro-5,6-di-O-benzyl-â-D-gulofuranosyl-p-tolyl-(R/S)-
sulfoxide (17a/17b). To a solution of 14 (410 mg, 0.91 mmol) in
CH2Cl2 (25 mL) at -78 °C was added m-CPBA (0.20 g, 0.82
mmol). After stirring for 2 h, the reaction mixture was warmed to
rt and stirred for 30 min. The solution was then washed with a
saturated aq solution of NaHCO3 (3 × 15 mL) and then water (15
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated to yield a crude oil that was purified by chromatography
(3:1 hexanes/EtOAc) to provide 17a (220 mg, 58%) and 17b (110
mg, 29%) as white semisolids. 17a: Rf 0.27 (2:1 hexanes/EtOAc);
1
[R]D +104.4 (c 0.6, CH2Cl2); H NMR (500 MHz, CDCl3, δH)
7.53-7.50 (m, 2H, Ar), 7.40-7.26 (m, 12H, Ar), 4.70 (d, 1H, J )
11.8 Hz, PhCH2), 4.68 (s, 1H, H-1), 4.64 (d, 1H, J ) 11.8 Hz,
PhCH2), 4.58 (d, 1H, J ) 12.0 Hz, PhCH2), 4.54 (d, 1H, J ) 12.0
Hz, PhCH2), 4.53 (dd, 1H, J ) 6.8, 0.7 Hz, H-4), 4.05 (d, 1H, J )
J. Org. Chem, Vol. 71, No. 26, 2006 9667

Bai and Lowary
2.8 Hz, H-2), 3.92 (dd, 1H, J ) 2.8, 0.7 Hz, H-3), 3.77 (ddd, 1H,
J ) 6.8, 5.0, 4.0 Hz, H-5), 3.71 (dd, 1H, J ) 10.8, 4.0 Hz, H-6),
concentrated to yield the crude product. Chromatography (2:1
hexane/EtOAc) yielded 21 (0.92 g, 61% over two steps) as a
1
3.69 (dd, 1H, J ) 10.8, 5.0 Hz, H-6), 2.42 (s, 3H, tolyl CH3); 13
C
colorless oil. Rf 0.43 (1:1 hexanes/EtOAc); H NMR (400 MHz,
NMR (125 MHz, CDCl3, δC) 142.0 (Ar), 138.4 (Ar), 137.9 (Ar),
137.2 (Ar), 130.1 (Ar × 2), 128.4 (Ar × 2), 128.3 (Ar × 2), 127.8
(Ar × 3), 127.7 (Ar × 2), 127.6 (Ar), 124.6 (Ar × 2), 96.3 (C-1),
81.5 (C-4), 78.0 (C-5), 73.6 (PhCH2), 73.1 (PhCH2), 70.2 (C-6),
56.0 (C-3), 55.1 (C-2), 21.4 (tolyl CH3). HRMS (ESI): [M + Na]
calcd for C27H28O5SNa, 487.1550; found, 487.1550. 17b: Rf 0.18
(2:1 hexanes/EtOAc); [R]D -176.8 (c 0.16, CH2Cl2); 1H NMR (500
MHz, CDCl3, δH) 7.56 (d, 2H, J ) 8.2 Hz, Ar), 7.36-7.26 (m,
12H, Ar), 4.82 (s, 1H, H-1), 4.66 (d, 1H, J ) 11.8 Hz, PhCH2),
4.60 (d, 1H, J ) 11.8 Hz, PhCH2), 4.55 (d, 1H, J ) 12.0 Hz,
PhCH2), 4.50 (d, 1H, J ) 12.0 Hz, PhCH2), 4.41 (dd, 1H, J ) 6.8,
0.8 Hz, H-4), 4.12 (d, 1H, J ) 2.8 Hz, H-2), 3.81 (dd, 1H, J ) 2.8,
0.8 Hz, H-3), 3.72-3.69 (m, 1H, H-5), 3.66-3.61 (m, 2H, H-6 ×
2), 2.41 (s, 3H, tolyl CH3); 13C NMR (125 MHz, CDCl3, δC) 142.3
(Ar), 138.5 (Ar), 136.5 (Ar), 129.9 (Ar), 128.4 (Ar × 2), 128.2
(Ar × 2), 127.8 (Ar × 2), 127.7 (Ar × 3), 127.6 (Ar × 2), 127.5
(Ar), 125.4 (Ar × 2), 94.6 (C-1), 82.6 (C-4), 78.0 (C-5), 73.5
(PhCH2), 73.0 (PhCH2), 70.4 (C-6), 56.4 (C-3), 56.0 (C-2), 21.5
(tolyl CH3). HRMS (ESI): [M + Na] calcd for C27H28O5S,
487.1550; found, 487.1551.
2,3-Anhydro-5,6-di-O-benzoyl-â-D-gulofuranosyl-p-tolyl-(R/
S)-sulfoxide (18a/18b). To a solution of 15 (360 mg, 0.75 mmol)
in CH2Cl2 (20 mL) at -78 °C was added m-CPBA (160 mg, 0.68
mmol). After stirring for 2 h, the reaction mixture was warmed to
rt and stirred for 30 min. The solution was washed with a saturated
aq solution of NaHCO3 (3 × 15 mL) and then water (3 × 15 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated
to yield a crude oil that was purified by chromatography (2:1
hexanes/EtOAc) to provide the diastereomers 18a (200 mg, 54%)
and 18b (120 mg, 32%) as white semisolids. 18a: Rf 0.18 (2:1
hexanes/EtOAc); [R]D +185.2 (c 0.3, CH2Cl2); 1H NMR (500 MHz,
CDCl3, δH) 8.08-8.05 (m, 2H, Ar), 8.03-8.00 (m, 2H, Ar), 7.60-
7.54 (m, 2H, Ar), 7.50 (d, 2H, J ) 8.2 Hz, Ar), 7.47-7.40 (m, 4H,
Ar), 7.34 (d, 2H, J ) 8.2 Hz, Ar), 5.72 (ddd, 1H, J ) 5.9, 5.9, 4.3
Hz, H-5), 4.78-4.67 (m, 4H, H-1, H-4, H-6 × 2), 4.08 (d, 1H, J
) 2.9 Hz, H-3), 3.98 (d, 1H, J ) 2.9 Hz, H-2), 2.40 (s, 3H, tolyl
CH3); 13C NMR (125 MHz, CDCl3, δC) 166.0 (CdO), 165.7
(CdO), 142.2 (Ar), 136.4 (Ar), 133.3 (Ar), 133.2 (Ar), 130.2 (Ar
× 2), 129.9 (Ar × 2), 129.7 (Ar × 2), 129.6 (Ar), 129.5 (Ar),
128.5 (Ar × 2), 128.4 (Ar × 2), 124.1 (Ar × 2), 95.9 (C-1), 78.6
(C-4), 71.0 (C-5), 63.1 (C-6), 55.6 (C-3), 54.9 (C-2), 21.4 (tolyl
CH3). HRMS (ESI): [M + Na] calcd for C27H24O7SNa, 515.1135;
found, 515.1136. 18b: Rf 0.09 (2:1 hexanes/EtOAc); [R]D -194.9
(c 0.47, CH2Cl2). 1H NMR (500 MHz, CDCl3, δH) 8.05-7.98 (m,
4H, Ar), 7.60-7.50 (m, 4H, Ar), 7.46-7.40 (m, 4H, Ar), 7.27-
7.23 (m, 2H, Ar), 5.63 (ddd, 1H, J ) 5.8, 5.8, 4.8 Hz, H-5), 4.80
(s, 1H, H-1), 4.69 (dd, 1H, J ) 5.8, 0.8 Hz, H-4), 4.67-4.60 (m,
2H, H-6 × 2), 4.22 (d, 1H, J ) 2.8 Hz, H-2), 4.03 (dd, 1H, J )
2.8, 0.8 Hz, H-3), 2.35 (s, 3H, tolyl CH3); 13C NMR (125 MHz,
CDCl3, δC) 166.0 (CdO), 165.7 (CdO), 142.5 (Ar × 2), 136.2
(Ar), 133.2 (Ar × 2), 129.9 (Ar × 2), 129.8 (Ar × 2), 129.7 (Ar
× 2), 129.5 (Ar), 128.5 (Ar × 2), 128.4 (Ar × 2), 125.2 (Ar × 2),
94.3 (C-1), 79.7 (C-4), 70.9 (C-5), 63.0 (C-6), 56.1 (C-2), 55.8
(C-3), 21.5 (tolyl CH3). HRMS (ESI): [M + H] calcd for
C27H25O7S, 493.1316; found, 493.1315.
CDCl3, δH) 5.57 (t, 0.35H, J ) 6.8 Hz, H-3R), 5.38 (ddd, 0.65H,
J ) 8.1, 4.4, 4.4 Hz, H-5â), 5.30 (s, 0.35H, H-1R), 5.24-5.19 (m,
0.35H, H-5R), 5.07-4.99 (m, 1.65H, H-2, H-3, H-2R), 4.92 (s,
0.65H, H-1â), 4.36 (dd, 0.35H, J ) 11.8, 4.5 Hz, H-6R), 4.33 (dd,
0.65H, J ) 12.0, 4.5 Hz, H-6â), 4.25-4.09 (m, 2H, H-4R, H-4â,
H-6R, H-6â), 3.39 (s, 1.95H, OCH3â), 3.37 (s, 1.05H, OCH3R),
2.14 (s, 1.95H, acyl CH3â), 2.13 (s, 1.05H, acyl CH3R), 2.11 (s,
3H, acyl CH3R, acyl CH3â), 2.09 (s, 1.95H, acyl CH3â), 2.07 (s,
1.05H, acyl CH3R), 2.06 (s, 1.95H, acyl CH3â), 2.05 (s, 1.05H,
acyl CH3R); 13C NMR (100 MHz, CDCl3, δC) 170.5 (CdO), 170.4
(CdO), 170.0 (CdO × 2), 169.9 (CdO × 2), 169.8 (CdO), 169.6
(CdO), 106.6 (C-1â), 100.5 (C-1R), 81.3 (C-2â), 79.9 (C-4â), 77.7
(C-4R), 76.5 (C-3â), 76.4 (C-3R), 73.6 (C-2R), 70.6 (C-5R), 69.3
(C-5â), 62.6 (C-6â), 62.2 (C-6R), 55.3 (OCH3R), 55.0 (OCH3â),
20.82 (acyl CH3), 20.8 (acyl CH3), 20.74 (acyl CH3), 20.7 (acyl
CH3), 20.66 (acyl CH3 × 2), 20.6 (acyl CH3 × 2). HRMS (ESI):
[M + Na] calcd for C15H22O10Na, 385.1104; found, 385.1105.
p-Tolyl 2,3,5,6-Tetra-O-acetyl-1-thio-R/â-D-galactofuranoside
(22). To a solution of p-thiocresol (2.24 g, 17.7 mmol) and 21 (5.82
g, 16.1 mmol) in dry CH2Cl2 (80 mL) was added BF3‚Et2O (6.1
mL, 48.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 3 h and then diluted with CH2Cl2 (100 mL), washed with a
saturated aq NaHCO3 solution (3 × 150 mL), dried (Na2SO4), and
concentrated. Chromatography (4:1 hexane/EtOAc) yielded 22 (5.51
g, 76%) in a 1:9 R:â ratio as a slightly yellow syrup. Rf 0.37 (4:1
hexanes/EtOAc); 1H NMR (500 MHz, CDCl3, δH) 7.41-7.36 (m,
2H, Ar), 7.12 (d, 2H, J ) 7.9 Hz, Ar), 5.52 (d, 0.1H, J ) 5.2 Hz,
H-1R), 5.46 (dd, 0.1H, J ) 5.2, 3.8 Hz, H-2R), 5.43 (d, 0.9H, J )
2.5 Hz, H-1â), 5.40-5.35 (m, 1H, H-5R, H-5â), 5.31 (dd, 0.1H, J
) 5.0, 3.8 Hz, H-3R), 5.21 (dd, 0.9H, J ) 2.7, 2.5 Hz, H-2â), 5.04
(dd, 0.9H, J ) 6.1, 2.7 Hz, H-3â), 4.46 (dd, 0.9H, J ) 6.1, 3.8 Hz,
H-4â), 4.40 (dd, 0.1H, J ) 12.0, 4.1 Hz, H-6R), 4.32 (dd, 0.9H, J
) 11.8, 4.6 Hz, H-6â), 4.22-4.18 (m, 0.1H, H-6R), 4.18 (dd, 0.9H,
J ) 11.8, 6.1 Hz, H-6â), 4.08 (dd, 0.1H, J ) 5.1, 5.0 Hz, H-4R),
2.33 (s, 3H, tolyl CH3), 2.17 (s, 0.3H, acyl CH3R), 2.14 (s, 0.3H,
acyl CH3R), 2.11 (s, 2.7H, acyl CH3â), 2.10 (s, 5.7H, acyl CH3),
2.07 (s, 0.3H, acyl CH3R), 2.40 (s, 2.7H, acyl CH3â); 13C NMR
(125 MHz, CDCl3, δC) 170.4 (CdO), 170.0 (CdO), 169.9
(CdO), 169.6 (CdO), 138.3 (Ar), 138.0 (Ar), 133.0 (Ar × 2), 132.7
(Ar × 2), 129.9 (Ar × 2), 129.8 (Ar × 2), 129.2 (Ar × 2), 90.7
(C-1â), 89.6 (C-1R), 81.2 (C-2â), 80.6 (C-2R), 79.6 (C-4â), 77.0
(C-4R), 76.5 (C-3â), 75.9 (C-3R), 69.7 (C-5R), 69.1 (C-5â), 62.6
(C-6R), 62.5 (C-6â), 21.1 (tolyl CH3), 20.8 (acyl CH3), 20.7 (acyl
CH3 × 3). HRMS (ESI): [M + Na] calcd for C21H26O9SNa,
477.1190; found, 477.1194.
p-Tolyl 1-Thio-â-D-galactofuranoside (23). To a solution of
22 (4.76 g, 10.5 mmol) in CH3OH (100 mL) and CH2Cl2 (100 mL)
was added solid NaOCH3 until the pH was ∼10. The solution was
allowed to stir at rt for 4 h and then neutralized with acetic acid.
The mixture was concentrated, and the resulting crude was purified
by chromatography (10:1 CH2Cl2/CH3OH) to yield the anomers
23 (2.41 g, 80%) and 24 (0.25 g, 8%) as white solids. Data for 23:
1
Rf 0.21 (10:1 CH2Cl2/CH3OH); [R]D -231.1 (c 0.8, CH3OH); H
NMR (400 MHz, CD3OD, δH) 7.42-7.38 (m, 2H, Ar), 7.14-7.10
(m, 2H, Ar), 5.15 (d, 1H, J ) 5.0 Hz, H-1), 4.07 (dd, 1H, J ) 7.6,
5.4 Hz, H-3), 3.96-3.10 (m, 2H, H-2, H-4), 3.71 (ddd, 1H, J )
6.9, 5.9, 2.9 Hz, H-5), 3.62-3.58 (m, 2H, H-6 × 2), 2.30 (s, 3H,
tolyl CH3); 13C NMR (100 MHz, CD3OD, δC) 138.8 (Ar), 133.7
(Ar × 2), 132.2 (Ar), 130.6 (Ar × 2), 93.3 (C-1), 83.1 (C-2), 83.0
(C-4), 77.8 (C-3), 72.0 (C-5), 64.6 (C-6), 21.1 (tolyl CH3). HRMS
(ESI): [M + Na] calcd for C13H18O5SNa, 309.0767; found,
309.0764.
Methyl 2,3,5,6-Tetra-O-acetyl-R/â-D-galactofuranoside (21).
D-Galactose diethyl dithioacetal 20 (1.2 g, 4.2 mmol) was dissolved
in DMF (8.4 mL), and CH3OH (250 µL) was added followed by
1,3-dibromo-5,5-dimethylhydantoin (1.2 g, 4.2 mmol). After being
stirred for 30 min, the solution was diluted with pyridine (30 mL).
Acetic anhydride (6 mL, 63 mmol) was added, and then the solution
was allowed to stir for 5 h at rt. The reaction mixture was then
poured into ice-H2O (150 mL) containing NaHCO3 (2.0 g) and
extracted with CH2Cl2 (2 × 150 mL). The organic layers were
combined and washed with a saturated aq NaHCO3 (200 mL)
solution and H2O (200 mL), then dried (Na2SO4), filtered, and
p-Tolyl 2,3-Anhydro-1-thio-â-D-gulofuranoside (33). To a
solution of 23 (1.95 g, 6.82 mmol) and trimethylorthoacetate (1.0
mL, 8.1 mmol) in THF (50 mL) was added p-toluenesulfonic acid
(0.025 g) at rt. The solution was stirred for 3 h and then neutralized
9668 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
with Et3N. TLC showed two new spots at Rf 0.50 (major) and Rf
0.42 (minor) (10:1 CH2Cl2/CH3OH). The mixture was then cooled
to 0 °C, followed by the addition of PPh3 (7.15 g, 27.3 mmol);
DIAD (5.6 mL, 27.3 mmol) was subsequently added dropwise at
0 °C over 10 min. The reaction mixture was warmed to rt over 60
min. TLC showed one major new spot at Rf 0.45 (4:1 hexanes/
EtOAc). The reaction mixture was then concentrated and redis-
solved in EtOAc (200 mL), followed by washing with a 0.3% aq
HCl solution (100 mL) until the previous spot disappeared and two
new spots formed at Rf 0.28 (major) and Rf 0.20 (minor) (15:1
CH2Cl2/CH3OH), which corresponded to the putative 5-O-acetyl
and 6-O-acetyl derivatives. The solution was dried (Na2SO4),
filtered, and concentrated to give a yellow oil, which was dissolved
in CH3OH (50 mL) and CH2Cl2 (50 mL) before solid NaOCH3
was added until the pH was ∼10. The solution was stirred at rt for
14 h, followed by neutralization with HOAc. The resulting mixture
was concentrated and purified by chromatography (2:1 hexanes/
EtOAc) to yield 33 (1.32 g, 72% over four steps) as a colorless
1H, J ) 10.5 Hz, PhCH2), 4.36 (s, 1H, H-2), 4.27 (d, 1H, J ) 5.2
Hz, H-4′), 3.92-3.86 (m, 2H, H-3, H-4), 3.83 (d, 1H, J ) 2.9 Hz,
H-2′), 3.81-3.79 (m, 3H, H-5, H-6 × 2), 3.76 (d, 1H, J ) 2.9 Hz,
H-3′), 3.28 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3, δC) 166.0
(CdO), 165.9 (CdO), 138.6 (Ar), 138.5 (Ar), 138.3 (Ar), 133.2
(Ar), 129.9 (Ar), 129.7 (Ar), 129.67 (Ar), 128.4 (Ar), 128.39 (Ar),
128.35 (Ar), 128.3 (Ar), 128.2 (Ar), 127.9 (Ar), 127.8 (Ar), 127.7
(Ar), 127.5 (Ar), 127.4 (Ar), 100.7 (C-1′), 100.1 (C-1), 79.2 (C-3),
75.1 (PhCH2), 74.7 (C-4′), 74.69 (C-4), 73.4 (PhCH2), 72.0 (C-2),
71.6 (C-5), 71.6 (PhCH2), 71.5 (C-5′), 69.4 (C-6), 63.4 (C-6′), 55.3
(C-3′), 54.8 (OCH3), 54.5 (C-2′). HRMS (ESI): [M + Na] calcd
for C48H48O12Na, 839.3038; found, 839.3041.
Methyl 2,3-Anhydro-5,6-di-O-benzoyl-R-D-gulofuranosyl-
(1f4)-2,3,6-tri-O-benzyl-â-D-galactopyranoside (61). The gly-
cosylation of sulfoxide 18 (241 mg, 0.49 mmol) and alcohol 45
(216 mg, 0.46 mmol) was carried out following the general protocol,
and after workup, the product was purified by chromatography (3:1
hexanes/EtOAc) to yield 61 (275 mg, 72%) as a white foam. Rf
1
1
oil. Rf 0.21 (2:1 hexanes/EtOAc); [R]D -19.1 (c 0.3, CH2Cl2); H
0.34 (2:1 hexanes/EtOAc); [R]D +23.7 (c 1.3, CH2Cl2); H NMR
NMR (500 MHz, CD3OD, δH) 7.45-7.42 (m, 2H, Ar), 7.15-7.12
(m, 2H, Ar), 5.45 (s, 1H, H-1), 3.93 (dd, 1H, J ) 6.2, 0.7 Hz,
H-4), 3.92 (d, 1H, J ) 2.9 Hz, H-2), 3.82 (dd, 1H, J ) 2.9, 0.7 Hz,
H-3), 3.79 (ddd, 1H, J ) 6.2, 6.2, 4.4 Hz, H-5), 3.66 (dd, 1H, J )
11.6, 4.4 Hz, H-6), 3.61 (dd, 1H, J ) 11.6, 6.2 Hz, H-6), 2.31 (s,
3H, tolyl CH3); 13C NMR (125 MHz, CD3OD, δC) 139.4 (Ar), 134.5
(Ar × 2), 130.8 (Ar × 2), 130.6 (Ar), 88.3 (C-1), 79.2 (C-4), 72.8
(C-5), 64.6 (C-6), 58.3 (C-2), 56.2 (C-3), 21.1 (tolyl CH3). HRMS
(ESI): [M + Na] calcd for C13H16O4SNa, 291.0662; found,
291.0660.
(500 MHz, CDCl3, δH) 8.09-7.99 (m, 4H, Ar), 7.59-7.54 (m, 2H,
Ar), 7.46-7.18 (m, 19H, Ar), 5.74 (ddd, 1H, J ) 6.6, 5.0, 3.8 Hz,
H-5′), 5.24 (s, 1H, H-1′), 4.92 (d, 1H, J ) 10.9 Hz, PhCH2), 4.75
(dd, 1H, J ) 12.3, 6.6 Hz, H-6′), 4.74 (d, 1H, J ) 10.9 Hz, PhCH2),
4.69 (dd, 1H, J ) 12.3, 3.8 Hz, H-6′), 4.67 (d, 1H, J ) 11.2 Hz,
PhCH2), 4.58 (d, 1H, J ) 11.2 Hz, PhCH2), 4.57 (d, 1H, J ) 3.2
Hz, H-4), 4.49 (d, 1H, J ) 12.0 Hz, PhCH2), 4.44 (d, 1H, J ) 12.0
Hz, PhCH2), 4.30 (d, 1H, J ) 7.7 Hz, H-1), 4.11 (d, 1H, J ) 5.0
Hz, H-4′), 3.80 (dd, 1H, J ) 10.7, 4.2 Hz, H-6), 3.74-3.66 (m,
2H, H-2, H-6), 3.69 (d, 1H, J ) 3.0 Hz, H-3′), 3.58 (s, 3H, OCH3),
3.59-3.56 (m, 1H, H-5), 3.51 (d, 1H, J ) 3.0 Hz, H-2′), 3.40 (dd,
1H, J ) 9.7, 3.2 Hz, H-3); 13C NMR (125 MHz, CDCl3, δC) 166.0
(CdO), 165.8 (CdO), 138.9 (Ar), 138.4 (Ar), 138.35 (Ar), 133.3
(Ar), 133.2 (Ar), 129.8 (Ar), 129.7 (Ar), 128.5 (Ar), 128.4 (Ar),
128.3 (Ar), 128.26 (Ar), 128.2 (Ar), 128.15 (Ar), 129.0 (Ar), 127.6
(Ar), 127.5 (Ar), 127.46 (Ar), 127.45 (Ar), 104.8 (C-1), 100.0 (C-
1′), 80.7 (C-3), 79.8 (C-2), 75.2 (PhCH2), 73.8 (C-5), 73.6 (PhCH2),
73.5 (C-4′), 73.4 (PhCH2), 71.2 (C-5′), 70.5 (C-6), 70.1 (C-4), 63.2
(C-6′), 57.0 (OCH3), 55.4 (C-2′), 53.3 (C-3′). HRMS (ESI): [M +
Na] calcd for C48H48O12Na, 839.3038; found, 839.3038.
Methyl R-D-Galactofuranosyl-(1f2)-R-L-rhamnopyranoside
(72). To a solution of compound 76 (37 mg, 0.06 mmol) in CH3OH
(2 mL) was added 10% Pd/C (5 mg), and the reaction mixture was
stirred under a hydrogen atmosphere for 5 h. The mixture was then
filtered through Celite and concentrated, and the residue was
purified on Iatrobeads (5:1 CH2Cl2/CH3OH) to yield compound 72
(19 mg, 94%) as a white foam. Rf 0.27 (5:1 CH2Cl2/CH3OH); [R]D
+38.7 (c 1.7, CH3OH); 1H NMR (500 MHz, CD3OD, δH) 4.90 (d,
1H, J ) 4.8 Hz, H-1′), 4.60 (d, 1H, J ) 1.6 Hz, H-1), 4.25 (dd,
1H, J ) 8.6, 7.5 Hz, H-3′), 3.92 (dd, 1H, J ) 8.6, 4.8 Hz, H-2′),
3.81-3.79 (m, 1H, H-2), 3.79 (dd, 1H, J ) 7.5, 1.8 Hz, H-4′),
3.64-3.57 (m, 4H, H-3, H-4, H-6′ × 2), 3.55 (dq, 1H, J ) 9.5, 6.3
Hz, H-5), 3.36-3.32 (m, 4H, H-5′, OCH3), 1.27 (d, 3H, J ) 6.3
Hz, H-6); 13C NMR (125 MHz, CD3OD, δC) 103.7 (C-1′), 101.2
(C-1), 82.6 (C-4′), 80.8 (C-2), 78.7 (C-2′), 74.7 (C-3′), 74.2 (C-
5′), 71.6 (C-3, C-4), 69.8 (C-5), 64.4 (C-6′), 55.3 (OCH3), 17.9
(C-6). HRMS (ESI): [M + Na] calcd for C13H24O10Na, 363.1262;
found, 363.1263.
Methyl 2,3-Anhydro-5,6-di-O-benzoyl-R-D-gulofuranosyl-
(1f2)-3,4-di-O-benzyl-R-L-rhamnopyranoside (59). The glyco-
sylation of thioglycoside 15 (472 mg, 0.99 mmol) and sugar
acceptor 43 (351 mg, 0.98 mmole) was carried out following the
general protocol, and the crude reaction mixture was purified by
chromatography (2:1 hexanes/EtOAc) to give disaccharide 59 (217
mg, 69%) as a colorless syrup. Rf 0.26 (2:1 hexanes/EtOAc); [R]D
1
+14.7 (c 2.5, CH2Cl2); H NMR (500 MHz, CDCl3, δH) 8.08 (d,
2H, J ) 8.4 Hz, Ar), 8.00 (d, 2H, J ) 8.4 Hz, Ar), 7.60-7.54 (m,
2H, Ar), 7.48-7.40 (m, 4H, Ar), 7.36-7.20 (m, 10H, Ar), 5.88-
5.84 (m, 1H, H-5′), 5.38 (s, 1H, H-1′), 4.97 (d, 1H, J ) 10.9 Hz,
PhCH2), 4.81 (br s, 1H, H-2), 4.77 (dd, 1H, J ) 12.1, 6.6 Hz, H-6′),
4.75 (s, 1H, H-1), 4.72 (dd, 1H, J ) 12.1, 4.0 Hz, H-6′), 4.68 (d,
1H, J ) 11.2 Hz, PhCH2), 4.63 (d, 1H, J ) 10.9 Hz, PhCH2), 4.50
(d, 1H, J ) 11.2 Hz, PhCH2), 4.20 (d, 1H, J ) 5.0 Hz, H-4′), 3.84
(dd, 1H, J ) 9.3, 3.2 Hz, H-3), 3.78 (d, 1H, J ) 2.9 Hz, H-2′),
3.69 (qd, 1H, J ) 9.2, 6.2 Hz, H-5), 3.63 (d, 1H, J ) 2.9 Hz,
H-3′), 3.50 (dd, 1H, J ) 9.3, 9.2 Hz, H-4), 3.39 (s, 3H, OCH3),
1.31 (d, 3H, J ) 6.2 Hz, H-6); 13C NMR (125 MHz, CDCl3, δC)
166.0 (CdO), 165.8 (CdO), 138.8 (Ar), 138.5 (Ar), 133.2 (Ar ×
2), 129.9 (Ar × 2), 129.8 (Ar), 129.7 (Ar × 2), 129.6 (Ar), 128.4
(Ar × 4), 128.3 (Ar × 2), 128.2 (Ar × 2), 127.9 (Ar × 2), 127.8
(Ar × 2), 127.5 (Ar), 127.4 (Ar), 100.8 (C-1), 99.9 (C-1′), 80.5
(C-4), 78.8 (C-3), 75.3 (PhCH2), 74.0 (C-4′), 72.1 (PhCH2), 70.9
(C-5′), 70.7 (C-2), 67.5 (C-5), 63.4 (C-6′), 55.4 (C-3′), 54.8 (OCH3),
53.5 (C-2′), 18.0 (C-6). HRMS (ESI): [M + Na] calcd for
C41H42O11Na, 733.2619; found, 733.2621.
Methyl 2,3-Anhydro-5,6-di-O-benzoyl-R-D-gulofuranosyl-
(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranoside (60). The cou-
pling of sulfoxide 18 (140 mg, 0.28 mmol) and acceptor 44 (110
mg, 0.24 mmol) was carried out following the general protocol,
and after workup, the product was purified by chromatography (2:1
hexanes/EtOAc) to give 60 (163 mg, 70%) as a white foam. Rf
Methyl R-D-Galactofuranosyl-(1f2)-R-D-mannopyranoside
(73). To a solution of 77 (10 mg, 0.014 mmol) in CH3OH (2 mL)
was added 10% Pd/C (3 mg), and the reaction mixture was stirred
under a hydrogen atmosphere for 12 h. The mixture was filtered
through Celite and concentrated to yield compound 73 (5 mg, 100%)
as a white foam. Rf 0.25 (4:1 CH2Cl2/CH3OH); [R]D +53.7 (c 0.5,
1
0.23 (2:1 hexanes/EtOAc); [R]D +36.9 (c 1.4, CH2Cl2); H NMR
1
(500 MHz, CDCl3, δH) 8.06-8.00 (m, 4H, Ar), 7.58-7.52 (m, 2H,
Ar), 7.45-7.14 (m, 19H, Ar), 5.81 (ddd, 1H, J ) 5.2, 5.2, 5.2 Hz,
H-5′), 5.40 (s, 1H, H-1′), 4.88 (s, 1H, H-1), 4.87 (d, 1H, J ) 10.5
Hz, PhCH2), 4.78 (d, 2H, J ) 5.2 Hz, H-6′ × 2), 4.74 (d, 1H, J )
11.5 Hz, PhCH2), 4.68 (d, 1H, J ) 12.0 Hz, PhCH2), 4.62 (d, 1H,
J ) 11.5 Hz, PhCH2), 4.56 (d, 1H, J ) 12.0 Hz, PhCH2), 4.50 (d,
CH3OH); H NMR (500 MHz, CD3OD, δH) 5.07 (d, 1H, J ) 1.7
Hz, H-1), 4.99 (d, 1H, J ) 4.7 Hz, H-1′), 4.19 (dd, 1H, J ) 8.6,
7.5 Hz, H-3′), 3.95 (dd, 1H, J ) 8.6, 4.7 Hz, H-2′), 3.86 (dd, 1H,
J ) 12.0, 1.8 Hz, H-6), 3.77 (dd, 1H, J ) 3.4, 1.7 Hz, H-2), 3.74
(dd, 1H, J ) 7.5, 3.1 Hz, H-4′), 3.74-3.67 (m, 2H, H-3, H-6),
3.64-3.58 (m, 1H, H-6′), 3.58-3.52 (m, 4H, H-5′, H-4, H-6′, H-5),
J. Org. Chem, Vol. 71, No. 26, 2006 9669

Bai and Lowary
3.39 (s, 3H, OCH3); 13C NMR (125 MHz, CD3OD, δC) 104.7 (C-
1′), 101.0 (C-1), 83.4 (C-4′), 81.9 (C-2), 78.9 (C-2′), 75.2 (C-3′),
75.0 (C-5), 72.8 (C-3), 72.0 (C-5′), 69.2 (C-4), 64.8 (C-6′), 62.8
(C-6), 55.6 (OCH3). HRMS (ESI): [M + Na] calcd for C13H24O11Na,
379.1211; found, 379.1210.
(PhCH2), 75.0 (C-5), 73.4 (PhCH2), 72.7 (PhCH2), 72.1 (PhCH2),
71.7 (C-5′), 71.4 (C-4), 69.0 (C-6), 64.5 (C-6′), 55.2 (OCH3). HRMS
(ESI): [M + Na] calcd for C41H48O11Na, 739.3089; found,
739.3081.
Methyl 3-O-Benzyl-R-D-galactofuranosyl-(1f4)-2,3,6-tri-O-
benzyl-â-D-galactopyranoside (78). Disaccharide 61 (404 mg, 0.49
mmol) was subjected to the general protocol to open the epoxide
ring, and the crude residue was purified by chromatography (3:1
hexanes/EtOAc) to give 78 (207 mg, 69%) as a colorless oil. Rf
Methyl R-D-Galactofuranosyl-(1f2)-R-D-galactofuranosyl-
(1f4)-â-D-galactopyranoside (74). To a solution of 83 (12 mg,
0.012 mmol) in CH3OH (2 mL) was added 10% Pd(OH)2/C (8 mg),
and the reaction mixture was stirred under a hydrogen atmosphere
for 12 h. The mixture was then filtered through Celite and
concentrated to yield 74 (6.5 mg, 100%) as a white foam. Rf 0.53
(1:4 CH2Cl2/CH3OH); [R]D +56.5 (c 0.5, CH3OH); 1H NMR (600
MHz, CD3OD, δH) 5.03 (d, 1H, J ) 4.7 Hz, H-1′), 5.01 (d, 1H, J
) 4.8 Hz, H-1′′), 4.43 (dd, 1H, J ) 8.9, 8.3 Hz, H-3′′), 4.24 (dd,
1H, J ) 8.5, 7.8 Hz, H-3′), 4.14 (d, 1H, J ) 7.6 Hz, H-1), 4.06
(dd, 1H, J ) 8.9, 4.8 Hz, H-2′′), 3.95 (dd, 1H, J ) 8.5, 4.7 Hz,
H-2′), 3.90 (d, 1H, J ) 2.1 Hz, H-4), 3.82 (dd, 1H, J ) 10.8, 8.1
Hz, H-6), 3.79 (d, 1H, J ) 8.3 Hz, H-4′′), 3.78 (dd, 1H, J ) 7.8,
3.5 Hz, H-4′), 3.73-3.69 (m, 1H, H-5′), 3.69 (dd, 1H, J ) 10.8,
5.8 Hz, H-6), 3.65-3.56 (m, 5H, H-6′ × 2, H-6′′ × 2, H-5′′), 3.53
(dd, 1H, J ) 8.1, 5.8 Hz, H-5), 3.51 (s, 3H, OCH3), 3.45-3.44
(m, 2H, H-2, H-3); 13C NMR (125 MHz, CD3OD, δC) 106.2 (C-
1), 103.1 (C-1′′), 102.3 (C-1′), 84.2 (C-2′′), 82.6 (C-4′), 81.6 (C-
4′′), 79.4 (C-4), 79.1 (C-2′), 76.2 (C-5), 75.4 (C-3′), 74.3 (C-2),
72.9 (C-3′′), 72.7 (C-5′), 72.5 (C-3), 71.5 (C-5′′), 64.3 (C-6′′), 64.2
(C-6′), 60.6 (C-6), 57.5 (OCH3). HRMS (ESI): [M + Na] calcd
for C19H34O16Na, 541.1739; found, 541.1739.
Methyl 3-O-Benzyl-R-D-galactofuranosyl-(1f2)-3,4-di-O-benz-
yl-R-L-rhamnopyranoside (76). Compound 59 (160 mg, 0.225
mmol) was subjected to the general epoxide-opening protocol, and
the resulting residue was purified by chromatography (2:1 hexanes/
EtOAc) to give 76 (80 mg, 65%) as a colorless oil. Rf 0.29 (1:1
hexanes/EtOAc); [R]D +22.3 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3, δH) 7.40-7.25 (m, 15H, Ar), 4.98 (d, 1H, J ) 3.8 Hz,
H-1′), 4.95 (d, 1H, J ) 10.9 Hz, PhCH2), 4.93 (d, 1H, J ) 11.1
Hz, PhCH2), 4.80 (d, 1H, J ) 11.8 Hz, PhCH2), 4.74 (d, 1H, J )
11.8 Hz, PhCH2), 4.69 (d, 1H, J ) 10.9 Hz, PhCH2), 4.68 (d, 1H,
J ) 11.1 Hz, PhCH2), 4.55 (d, 1H, J ) 1.8 Hz, H-1), 4.28-4.24
(m, 2H, H-2′, H-4′), 4.00-3.96 (m, 1H, H-3′), 4.96-4.94 (m, 1H,
H-2), 3.89 (dd, 1H, J ) 9.4, 3.0 Hz, H-3), 3.78 (br s, 1H, OH),
3.67 (qd, 1H, J ) 9.5, 6.3 Hz, H-5), 3.62-3.59 (m, 1H, H-5′),
3.46 (dd, 1H, J ) 9.5, 9.4 Hz, H-4), 3.40 (dd, 1H, J ) 12.3, 4.3
Hz, H-6′), 3.55-3.51 (m, 4H, H-6′, OCH3), 1.60 (br s, 2H, OH ×
2), 1.30 (d, 3H, J ) 6.3 Hz, H-6 × 3); 13C NMR (125 MHz, CDCl3,
δC) 138.2 (Ar), 138.1 (Ar), 137.3 (Ar), 128.5 (Ar × 2), 128.4 (Ar
× 4), 128.1 (Ar), 128.0 (Ar × 2), 127.9 (Ar × 2), 127.8 (Ar),
127.7 (Ar × 3), 103.4 (C-1′), 99.1 (C-1), 82.6 (C-4′), 82.3 (C-3′),
80.6 (C-4), 78.5 (C-3), 77.7 (C-2′), 77.5 (C-2), 75.5 (PhCH2), 72.8
(PhCH2), 72.4 (PhCH2), 71.2 (C-5′), 67.9 (C-5), 65.0 (C-6′), 54.8
(OCH3), 18.0 (C-6). HRMS (ESI): [M + Na] calcd for C34H42O10Na,
633.2670; found, 633.2671.
1
0.55 (1:1 hexanes/EtOAc); [R]D +29.4 (c 1.5, CH2Cl2); H NMR
(600 MHz, CDCl3, δH) 7.42-7.25 (m, 20H, Ar), 4.97 (d, 1H, J )
5.0 Hz, H-1′), 4.93 (d, 1H, J ) 11.4 Hz, PhCH2), 4.90 (dd, 1H, J
) 10.9 Hz, PhCH2), 4.86 (d, 1H, J ) 10.9 Hz, PhCH2), 4.78 (d,
1H, J ) 12.5, PhCH2), 4.76 (d, 1H, J ) 12.5 Hz, PhCH2), 4.65 (d,
1H, J ) 11.4 Hz, PhCH2), 4.54 (d, 1H, J ) 11.8 Hz, PhCH2), 4.51
(d, 1H, J ) 11.8 Hz, PhCH2), 4.25 (d, 1H, J ) 7.6 Hz, H-1), 4.24
(dd, 1H, J ) 7.6, 7.5 Hz, H-3′), 4.18-4.15 (m, 1H, H-2′), 4.13 (d,
1H, J ) 11.5 Hz, OH), 4.08 (d, 1H, J ) 3.0 Hz, H-4), 3.88 (dd,
1H, J ) 7.5, 1.5 Hz, H-4′), 3.70 (dd, 1H, J ) 9.2, 9.1 Hz, H-6),
3.68 (dd, 1H, J ) 9.9, 7.6 Hz, H-2), 3.59 (dd, 1H, J ) 9.2, 5.4 Hz,
H-6), 3.59-3.55 (m, 1H, H-5′), 3.53 (s, 3H, OCH3), 3.50 (dd, 1H,
J ) 9.1, 5.4 Hz, H-5), 3.47 (dd, 1H, J ) 9.9, 3.0 Hz, H-3), 3.43-
3.32 (m, 2H, H-6′ × 2), 2.75 (d, 1H, J ) 10.5 Hz, OH); 13C NMR
(125 MHz, CDCl3, δC) 138.5 (Ar), 138.1 (Ar), 137.3 (Ar), 137.2
(Ar), 128.6 (Ar), 128.5 (Ar), 128.4 (Ar), 128.35 (Ar), 128.2 (Ar),
128.1 (Ar), 128.0 (Ar), 127.95 (Ar), 127.8 (Ar), 127.7 (Ar), 105.1
(C-1), 103.6 (C-1′), 82.6 (C-3′), 81.4 (C-4′), 79.6 (C-2), 79.59 (C-
3), 78.0 (C-2′), 75.6 (C-4), 75.4 (PhCH2), 73.7 (PhCH2), 72.9
(PhCH2), 72.5 (PhCH2), 72.3 (C-5), 70.8 (C-5′), 66.7 (C-6), 65.0
(C-6′), 57.3 (OCH3). HRMS (ESI): [M + Na] calcd for C41H48O11Na,
739.3089; found, 739.3091.
Methyl 3-O-Benzyl-5,6-O-isopropylidene-R-D-galactofurano-
syl-(1f4)-2,3,6-tri-O-benzyl-â-D-galactopyranoside (79). To a
mixture of compound 78 (198 mg, 0.28 mmol) and 2,2-dimeth-
oxypropane (0.27 mL, 2.2 mmol) in dry acetone (5 mL) was added
p-TsOH (2 mg), and the reaction mixture was stirred at rt for 4 h.
Two drops of Et3N were added, and the reaction mixture was
concentrated. Column chromatography (3:1 hexanes/EtOAc) of the
residue gave the disaccharide 79 (0.185 g, 89%) as a colorless oil.
Rf 0.38 (2:1 hexanes/EtOAc); [R]D +45.9 (c 0.6, CH2Cl2); 1H NMR
(500 MHz, CDCl3, δH) 7.41-7.24 (m, 20H, Ar), 5.19 (d, 1H, J )
4.8 Hz, H-1′), 4.98 (d, 1H, J ) 13.3 Hz, PhCH2), 4.91 (d, 1H, J )
11.5 Hz, PhCH2), 4.88 (d, 1H, J ) 11.1 Hz, PhCH2), 4.80 (d, 1H,
J ) 11.1 Hz, PhCH2), 4.62 (d, 1H, J ) 13.3 Hz, PhCH2), 4.59 (d,
1H, J ) 11.5 Hz, PhCH2), 4.53 (s, 2H, PhCH2), 4.36 (ddd, 1H, J
) 8.0, 7.0, 7.0 Hz, H-5′), 4.27 (d, 1H, J ) 3.0 Hz, H-4), 4.24 (d,
1H, J ) 7.5 Hz, H-1), 4.17 (dd, 1H, J ) 6.8, 4.8 Hz, H-2′), 3.90
(dd, 1H, J ) 8.0, 7.0 Hz, H-4′), 3.84-3.74 (m, 2H, H-6′ × 2),
3.74 (dd, 1H, J ) 7.0, 6.8 Hz, H-3′), 3.68-3.59 (m, 2H, H-6 × 2),
3.57 (dd, 1H, J ) 9.8, 7.5 Hz, H-2), 3.54 (s, 3H, OCH3), 3.49 (dd,
1H, J ) 8.7, 5.5 Hz, H-5), 3.43 (dd, 1H, J ) 9.8, 3.0 Hz, H-3),
1.39 (s, 3H, isopropylidene CH3), 1.21 (s, 3H, isopropylidene CH3);
13C NMR (125 MHz, CDCl3, δC) 138.6 (Ar), 138.5 (Ar), 137.7
(Ar), 137.2 (Ar), 128.6 (Ar), 128.5 (Ar), 128.2 (Ar), 128.16 (Ar),
128.1 (Ar), 128.0 (Ar), 127.9 (Ar), 127.6 (Ar), 127.56 (Ar), 127.3
(Ar), 109.5 (isopropylidene C), 105.0 (C-1), 103.0 (C-1′), 83.3 (C-
3′), 82.3 (C-4′), 78.8 (C-3), 78.7 (C-2), 78.33 (C-2′), 78.30 (C-5′),
75.0 (PhCH2), 73.7 (PhCH2), 72.4 (C-5), 72.1 (C-4), 71.9 (PhCH2),
70.5 (PhCH2), 67.0 (C-6), 65.0 (C-6′), 57.2 (OCH3), 26.7 (isopro-
pylidene CH3), 25.3 (isopropylidene CH3). HRMS (ESI): [M +
Na] calcd for C44H52O11Na, 779.3402; found, 779.3404.
Methyl 3-O-Benzyl-R-D-galactofuranosyl-(1f2)-3,4,6-tri-O-
benzyl-R-D-mannopyranoside (77). Epoxide 60 (80 mg, 0.098
mmol) was opened following the general protocol, and the product
was purified by chromatography (1:2 hexanes/EtOAc) to yield 77
(41 mg, 55%) as a colorless oil. Rf 0.33 (1:2 hexanes/EtOAc); [R]D
1
+18.1 (c 1.0, CH2Cl2); H NMR (500 MHz, CDCl3, δH) 7.40-
7.18 (m, 20H, Ar), 4.98 (d, 1H, J ) 4.8 Hz, H-1′), 4.96 (d, 1H, J
) 1.6 Hz, H-1), 4.89 (d, 1H, J ) 11.3 Hz, PhCH2), 4.83 (d, 1H, J
) 10.9 Hz, PhCH2), 4.69-4.55 (m, 5H, PhCH2), 4.52 (d, 1H, J )
10.9 Hz, PhCH2), 4.31 (dd, 1H, J ) 6.4, 4.8 Hz, H-2′), 4.19 (dd,
1H, J ) 6.4, 6.1, Hz, H-3′), 4.01 (dd, 1H, J ) 6.1, 3.7 Hz, H-4′),
3.96-3.92 (m, 1H, H-3), 3.82-3.80 (m, 1H, H-2), 3.80-3.76 (m,
2H, H-4, H-5), 3.76-3.67 (m, 3H, H-6 × 2, H-5′), 3.62-3.54 (m,
2H, H-6′ × 2), 3.36 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3,
δC) 138.2 (Ar), 138.1 (Ar), 138.0 (Ar), 137.7 (Ar), 128.6 (Ar), 128.4
(Ar), 128.37 (Ar), 128.0 (Ar), 127.99 (Ar), 127.9 (Ar), 127.8 (Ar),
127.77 (Ar), 127.7 (Ar), 127.6 (Ar), 104.4 (C-1′), 99.1 (C-1), 83.5
(C-3′), 83.2 (C-4′), 79.0 (C-3), 78.6 (C-2′), 78.1 (C-2), 75.2
Methyl 2,3-Anhydro-5,6-di-O-benzoyl-R-D-gulofuranosyl-
(1f2)-3-O-benzyl-5,6-O-isopropylidene-R-D-galactofuranosyl-
(1f4)-2,3,6-tri-O-benzyl-â-D-galactopyranoside (80). The gly-
cosylation of disaccharide 79 (283 mg, 0.37 mmol) and donor 18
(553 mg, 1.12 mmol) was carried out following the general protocol,
and after workup, the product was purified by column chromatog-
raphy (2:1 hexanes/EtOAc) to yield 80 (243 mg, 59%) as a white
foam. Rf 0.30 (3:2 hexanes/EtOAc); [R]D +48.6 (c 0.5, CH2Cl2);
9670 J. Org. Chem., Vol. 71, No. 26, 2006

2,3-Anhydrosugars in Glycoside Bond Synthesis
1H NMR (600 MHz, CD2Cl2, δH) 8.04-7.97 (m, 4H, Ar), 7.58-
7.54 (m, 2H, Ar), 7.45-7.38 (m, 6H, Ar), 7.35-7.20 (m, 18H,
Ar), 5.75 (ddd, 1H, J ) 6.4, 5.2, 4.0 Hz, H-5′′), 5.14 (d, 1H, J )
4.3 Hz, H-1′), 5.06 (s, 1H, H-1′′), 4.92 (d, 1H, J ) 12.8 Hz, PhCH2),
4.82 (d, 1H, J ) 11.4 Hz, PhCH2), 4.81 (d, 1H, J ) 10.8 Hz,
PhCH2), 4.76 (d, 1H, J ) 10.8 Hz, PhCH2), 4.76-4.70 (m, 2H,
H-6′′ × 2), 4.61 (d, 1H, J ) 12.8 Hz, PhCH2), 4.57 (d, 1H, J )
11.4 Hz, PhCH2), 4.56 (d, 1H, J ) 12.1 Hz, PhCH2), 4.49 (d, 1H,
J ) 12.1 Hz, PhCH2), 4.44 (dd, 1H, J ) 6.6, 4.3 Hz, H-2′), 4.35
(ddd, 1H, J ) 6.8, 6.8, 6.8 Hz, H-5′), 4.24 (d, 1H, J ) 7.6 Hz,
H-1), 4.19 (dd, 1H, J ) 5.2, 0.9 Hz, H-4′′), 4.12 (d, 1H, J ) 3.0
Hz, H-4), 4.00 (dd, 1H, J ) 6.7, 6.6 Hz, H-3′), 3.82-3.79 (m, 2H,
H-6′, H-3′′), 3.76-3.73 (m, 2H, H-6′, H-4′), 3.69 (d, 1H, J ) 3.1
Hz, H-2′′), 3.66-3.63 (m, 3H, H-2, H-6 × 2), 3.52 (s, 3H, OCH3),
3.52-3.50 (m, 1H, H-5), 3.40 (dd, 1H, J ) 9.8, 3.0 Hz, H-3), 1.34
2H, H-6′, H-4′′), 3.77 (dd, 1H, J ) 9.2, 7.0 Hz, H-6′), 3.71 (dd,
1H, J ) 9.8, 7.6 Hz, H-2), 3.69-3.65 (m, 1H, H-5′′), 3.59-3.49
(m, 5H, H-6′′ × 2, H-6 × 2, H-5), 3.33 (s, 3H, OCH3), 3.44 (dd,
1H, J ) 9.8, 3.0 Hz, H-3), 2.84 (br s, 1H, OH), 1.39 (s, 3H,
isopropylidene CH3), 1.16 (s, 3H, isopropylidene CH3); 13C NMR
(125 MHz, CDCl3, δC) 138.8 (Ar), 138.4 (Ar), 137.9 (Ar), 137.6
(Ar), 137.1 (Ar), 128.6 (Ar), 128.56 (Ar), 128.5 (Ar), 128.4 (Ar),
128.3 (Ar), 128.1 (Ar), 127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 127.54
(Ar), 127.5 (Ar), 109.2 (isopropylidene C), 105.0 (C-1), 103.0 (C-
1′′), 101.2 (C-1′), 82.9 (C-3′′), 82.7 (C-2′), 82.1 (C-4′′), 82.0 (C-
4′), 81.9 (C-3′), 79.8 (C-3), 79.0 (C-2), 77.7 (C-2′′), 76.5 (C-5′),
75.3 (PhCH2), 73.8 (PhCH2), 72.4 (C-5), 72.3 (C-5′′), 72.1 (PhCH2),
71.8 (PhCH2), 71.3 (C-4), 71.2 (PhCH2), 67.2 (C-6), 65.1 (C-6′),
64.2 (C-6′′), 57.2 (OCH3), 26.4 (isopropylidene CH3), 24.5 (iso-
propylidene CH3). HRMS (ESI): [M + Na] calcd for C57H68O16Na,
1031.4405; found, 1031.4407.
(s, 3H, isopropylidene CH3), 1.20 (s, 3H, isopropylidene CH3); 13
C
NMR (125 MHz, CD2Cl2, δC) 166.3 (CdO), 166.1 (CdO), 139.6
(Ar), 139.3 (Ar), 138.6 (Ar), 138.4 (Ar), 133.7 (Ar), 133.6 (Ar),
130.2 (Ar), 130.1 (Ar), 130.0 (Ar), 128.9 (Ar), 128.83 (Ar), 128.8
(Ar), 128.6 (Ar), 128.55 (Ar), 128.5 (Ar), 128.3 (Ar), 128.24 (Ar),
128.2 (Ar), 128.1 (Ar), 128.0 (Ar), 127.7 (Ar), 127.6 (Ar), 109.6
(isopropylidene C), 105.4 (C-1), 102.5 (C-1′), 101.0 (C-1′′), 82.2
(C-2′), 81.54 (C-3′), 81.5 (C-4′), 80.5 (C-3), 79.4 (C-2), 78.6 (C-
5′), 75.5 (C-4′′), 75.3 (PhCH2), 73.7 (PhCH2), 73.6 (C-4), 73.55
(C-5), 72.4 (PhCH2), 71.8 (C-5′′), 71.7 (PhCH2), 69.2 (C-6), 65.4
(C-6′), 63.7 (C-6′′), 57.3 (OCH3), 55.7 (C-2′′), 54.4 (C-3′′), 27.0
(isopropylidene CH3), 25.6 (isopropylidene CH3). HRMS (ESI):
[M + Na] calcd for C64H68O17Na, 1131.4354; found, 1131.4351.
Methyl 2,3-Anhydro-5,6-di-O-benzoyl-R-D-gulofuranosyl-
(1f2)-3-O-benzyl-R-D-galactofuranosyl-(1f4)-2,3,6-tri-O-ben-
zyl-â-D-galactopyranoside (81). Rf 0.12 (3:2 hexanes/EtOAc); [R]D
Methyl 3-O-Benzyl-R-D-galactofuranosyl-(1f2)-3-O-benzyl-
R-D-galactofuranosyl-(1f4)-2,3,6-tri-O-benzyl-â-D-galactopyra-
noside (83). A solution of compound 82 (49 mg, 0.049 mmol) in
HOAc/H2O/THF (5:3:2) was stirred at 50 °C for 12 h. The reaction
mixture was concentrated, and the resulting residue was purified
by chromatography (1:1 hexanes/EtOAc) to give 83 (38 mg, 81%)
as a colorless syrup. Rf 0.4 (1:3 hexanes/EtOAc); [R]D +50.7 (c
1
0.4, CH3OH); H NMR (600 MHz, CD3OD, δH) 7.40-7.25 (m,
25H, Ar), 5.12 (d, 2H, J ) 4.4 Hz, H-1′, H-1′′), 4.86-4.82 (m,
4H, PhCH2), 4.73 (d, 1H, J ) 11.1 Hz, PhCH2), 4.71 (d, 1H, J )
12.5 Hz, PhCH2), 4.65 (d, 1H, J ) 11.7 Hz, PhCH2), 4.64 (d, 1H,
J ) 11.1 Hz, PhCH2), 4.59 (d, 1H, J ) 11.7 Hz, PhCH2), 4.54 (d,
1H, J ) 11.1 Hz, PhCH2), 4.53 (dd, 1H, J ) 6.8, 6.4 Hz, H-3′′),
4.27 (dd, 1H, J ) 6.8, 4.4 Hz, H-2′′), 4.26 (d, 1H, J ) 7.7 Hz,
H-1), 4.20 (dd, 1H, J ) 6.6, 4.4 Hz, H-2′), 4.12 (dd, 1H, J ) 6.6,
6.4 Hz, H-3′), 4.07 (d, 1H, J ) 3.0 Hz, H-4), 4.02 (dd, 1H, J )
6.4, 2.5 Hz, H-4′′), 3.90 (dd, 1H, J ) 6.4, 6.0 Hz, H-4′), 3.84 (dd,
1H, J ) 9.3, 7.7 Hz, H-6), 3.77 (ddd, 1H, J ) 6.3, 6.1, 6.0 Hz,
H-5′), 3.65-3.58 (m, 3H, H-2, H-6, H-5), 3.57-3.52 (m, 3H, H-3,
H-6′, H-5′′), 3.48 (s, 3H, OCH3), 3.43 (dd, 1H, J ) 11.5, 6.3 Hz,
H-6′), 3.40-3.34 (m, 2H, H-6” × 2); 13C NMR (125 MHz, CD3OD,
δC) 140.3 (Ar), 139.8 (Ar), 139.6 (Ar), 139.5 (Ar), 139.0 (Ar), 129.5
(Ar), 129.44 (Ar), 129.4 (Ar), 129.3 (Ar), 129.23 (Ar), 129.2 (Ar),
129.15 (Ar), 129.1 (Ar), 129.05 (Ar), 129.02 (Ar), 129.0 (Ar),
128.96 (Ar), 128.9 (Ar), 128.7 (Ar), 128.5 (Ar), 106.2 (C-1), 104.1
(C-1′′), 103.0 (C-1′), 83.9 (C-3′), 82.7 (C-4′), 82.3 (C-2′′), 82.0
(C-3′′), 81.9 (C-4′′), 81.3 (C-3), 80.8 (C-2), 78.8 (C-2′), 77.3 (C-
4), 76.3 (PhCH2), 74.4 (PhCH2), 74.3 (C-5′), 73.93 (C-5), 73.9
(PhCH2), 73.6 (PhCH2), 73.0 (PhCH2), 72.9 (C-5′′), 68.7 (C-6),
64.2 (C-6′, C-6′′), 57.6 (OCH3). HRMS (ESI): [M + Na] calcd
for C54H64O16Na, 991.4087; found, 991.4088.
1
+36.7 (c 0.4, CH2Cl2); H NMR (600 MHz, CDCl3, δH) 8.02-
8.00 (m, 4H, Ar), 7.60-7.52 (m, 2H, Ar), 7.45-7.25 (m, 22H,
Ar), 7.28-7.20 (m, 2H, Ar), 5.77 (br s, 1H, H-5′′), 5.02 (d, 1H, J
) 4.3 Hz, H-1′), 4.93 (s, 1H, H-1”), 4.90-4.80 (m, 3H, PhCH2),
4.77 (d, 1H, J ) 10.6 Hz, PhCH2), 4.77-4.73 (m, 1H, H-6′′), 4.70
(d, 1H, J ) 12.3 Hz, PhCH2), 4.70-4.64 (m, 2H, H-6′′, H-2′),
4.64 (d, 1H, J ) 11.5 Hz, PhCH2), 4.55 (d, 1H, J ) 12.3 Hz,
PhCH2), 4.48 (d, 1H, J ) 12.3 Hz, PhCH2), 4.42 (dd, 1H, J ) 7.3,
7.2 Hz, H-3′), 4.21 (d, 1H, J ) 7.6 Hz, H-1), 4.05 (d, 1H, J ) 5.0
Hz, H-4′′), 3.82-3.77 (m, 2H, H-4, H-4′), 3.74 (br s, 1H, H-3′′),
3.72-3.62 (m, 4H, H-2, H-5′, H-6′ × 2), 3.54 (s, 1H, H-2′′), 3.54
(s, 3H, OCH3), 3.46 (dd, 1H, J ) 11.4, 4.0 Hz, H-6), 3.42-3.35
(m, 3H, H-5, H-3, H-6); 13C NMR (125 MHz, CDCl3, δC) 166.0
(CdO), 165.7 (CdO), 138.7 (Ar), 138.4 (Ar), 138.3 (Ar), 137.5
(Ar), 133.4 (Ar), 133.3 (Ar), 129.8 (Ar), 129.7 (Ar), 129.6 (Ar),
129.5 (Ar), 128.5 (Ar), 128.47 (Ar), 128.44 (Ar), 128.4 (Ar), 128.3
(Ar), 128.28 (Ar), 128.2 (Ar), 128.0 (Ar), 127.9 (Ar), 127.7 (Ar),
127.63 (Ar), 127.6 (Ar), 127.55 (Ar), 104.9 (C-1), 103.9 (C-1′),
99.9 (C-1′′), 80.5 (C-4′), 80.4 (C-3′), 80.2 (C-2′, C-3), 80.1 (C-2),
79.3 (C-4), 75.4 (PhCH2), 74.5 (C-4′′), 73.7 (C-5), 73.3 (PhCH2),
72.8 (PhCH2), 72.6 (PhCH2), 71.3 (C-5′, C-5′′), 69.1 (C-6′), 64.6
(C-6), 63.2 (C-6′′), 57.1 (OCH3), 55.2 (C-2′′), 53.4 (C-3′′). HRMS
(ESI): [M + Na] calcd for C61H64O17Na, 1091.4034; found,
1091.4036.
Acknowledgment. This work was supported by the Alberta
Ingenuity Centre for Carbohydrate Science, The University of
Alberta, and The Natural Sciences and Engineering Research
Council of Canada.
Methyl 3-O-Benzyl-R-D-galactofuranosyl-(1f2)-3-O-benzyl-
5,6-O-isopropylidene-R-D-galactofuranosyl-(1f4)-2,3,6-tri-O-
benzyl-â-D-galactopyranoside (82). Compound 80 (110 mg, 0.1
mmol) was subjected to the general protocol to open the epoxide,
and after workup, the product was purified by chromatography (1:1
hexanes/EtOAc) to give 82 (61 mg, 61%) as a colorless syrup. Rf
Note Added after ASAP Publication. Due to an oversight
by the corresponding author, the preparation of 21 in Scheme
1 and in the Experimental Section was incorrectly described in
the version published ASAP November 23, 2006; the corrected
version was published ASAP November 29, 2006.
1
0.29 (1:1 hexanes/EtOAc); [R]D +57.0 (c 0.6 CH2Cl2); H NMR
(500 MHz, CDCl3, δH) 7.42-7.26 (m, 25H, Ar), 5.16 (d, 1H, J )
4.2 Hz, H-1′), 4.96 (d, 1H, J ) 4.9 Hz, H-1′′), 4.90-4.86 (m, 3H,
PhCH2), 4.82 (d, 1H, J ) 11.4 Hz, PhCH2), 4.65 (d, 1H, J ) 11.4
Hz, PhCH2), 4.63-4.58 (m, 4H, PhCH2), 4.46 (d, 1H, J ) 11.8
Hz, PhCH2), 4.32 (d, 1H, J ) 3.0 Hz, H-4), 4.27 (d, 1H, J ) 7.6
Hz, H-1), 4.24-4.19 (m, 2H, H-2′′, H-5′), 4.14-4.06 (m, 3H, H-3′,
H-3′′, H-2′), 3.97 (dd, 1H, J ) 6.0, 4.8 Hz, H-4′), 3.94-3.89 (m,
Supporting Information Available: Details on the synthesis
of 34-37, data for additional new compounds not included above,
and 1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO061713O
J. Org. Chem, Vol. 71, No. 26, 2006 9671