Use of Acyclic Glycosyl Donors for Furanoside Synthesis

Article abstract of DOI:10.1021/jo9618583

Treatment of the peracetylated ethyl dithioacetals of D-glucose, D-galactose, and D-mannose with acetyl chloride and boron trifluoride diethyl etherate at reflux yields the known acyclic 1-chlorol-(ethylthio) derivatives. These compounds are shown to effectively glycosylate a variety of carbohydrate acceptors using silver trifluoromethanesulfonate as the promotor, affording stereospecifically the corresponding acyclic O,S-acetals in good to excellent yield. Furthermore, following deacetylation, treatment of these O,S-acetals with a mixture of mercuric salts in either methanol or dimethylformamide gives rise to disaccharides terminating in D-furanosyl residues.

Full text of DOI:10.1021/jo9618583

1234
J . Org. Chem. 1997, 62, 1234-1239
Use of Acyclic Glycosyl Don or s for F u r a n osid e Syn th esis
J oseph C. McAuliffe and Ole Hindsgaul*
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
Received October 1, 1996X
Treatment of the peracetylated ethyl dithioacetals of D-glucose, D-galactose, and D-mannose with
acetyl chloride and boron trifluoride diethyl etherate at reflux yields the known acyclic 1-chloro-
1-(ethylthio) derivatives. These compounds are shown to effectively glycosylate a variety of
carbohydrate acceptors using silver trifluoromethanesulfonate as the promotor, affording stereospe-
cifically the corresponding acyclic O,S-acetals in good to excellent yield. Furthermore, following
deacetylation, treatment of these O,S-acetals with a mixture of mercuric salts in either methanol
or dimethylformamide gives rise to disaccharides terminating in D-furanosyl residues.
Sch em e 1
In tr od u ction
Complex carbohydrates play a crucial role in many
biochemical processes including the modulation of en-
zyme and hormone activity, adhesion to host cells by
pathogens, and the response of tissues to wounding.1,2
The physical properties and inherent structural diversity
of carbohydrates enable this class of biomolecules to store
and transmit cellular information through their recogni-
tion by carbohydrate-binding proteins.3 A better under-
standing of this intercellular currency may allow the
development of new strategies for the effective treatment
of a variety of disorders. The efficient synthesis of pu-
tative carbohydrate ligands and their analogues is a
prerequisite for understanding their roles in information
transfer.
Despite the significant advances made in the last few
decades, the chemical synthesis of carbohydrates remains
a labor-intensive process, often involving tedious ma-
nipulations of protective groups and resulting in low
overall yields.4,5 Additional complications include the low
reactivity of certain carbohydrate alcohols and poor
stereoselectivity encountered in glycoside bond formation.
While many strategies have evolved to address these
problems with regard to pyranoside synthesis, methods
for the construction of the furanosidic linkage have only
recently begun to attract significant attention. This is
due primarily to the current interest in the chemistry6-12
and biology13 of â-D-galactofuranosides owing to the
widespread occurrence of this moiety in lower organisms.
Simple alkyl furanosides have been prepared from
sugar dithioacetals by means of a process involving
transformation into an O,S-acetal,14,15 followed by cy-
clization upon treatment with a thiophilic promoter
(Scheme 1).16,17 There is considerable scope for the
further extension of this type of methodology. For
example, dithioacetals and their equivalents, in effect
potential acyclic glycosyl donors, have not previously been
used to glycosylate sugar alcohols and may offer advan-
tages over cyclic donors. In addition, an O,S-acetal
(Scheme 2) has the potential to form either a five-, six-,
or seven-membered ring upon cyclization. Such a diver-
gent glycosylation strategy would clearly complement the
current “parallel” approach and warrants investigation.
In this paper, we demonstrate the efficient glycosylation
of carbohydrate acceptors by the known 1-chloro-1-
(ethylthio)-2,3,4,5,6-penta-O-acetyl derivatives of D-glu-
cose, D-galactose, and D-mannose.14,15,18 The O,S-acetals
so obtained are readily converted into D-furanosides by
means of a convenient two-pot procedure.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Varki, A. Glycobiology 1993, 3, 97.
(2) Dwek, R. A. Chem. Rev. 1996, 96, 683.
(3) Drickamer, K. In Molecular Glycobiology; Fukuda, M., Hinds-
gaul, O., Eds; IRL: Oxford, 1994; Chapter 2, pp 53-87.
(4) Toshima, K; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
(5) Boons, G.-J . Tetrahedron 1996, 52, 1095.
(6) van Heeswijk, W. A. R.; Visser, H. G. J .; Vliegenthart, J . F. G.
Carbohydr. Res. 1977, 59, 81.
Resu lts a n d Discu ssion
(7) Sugawara, F.; Nakayama, H.; Ogawa, T. Agric. Biol. Chem. 1986,
50, 1557.
Sugar dithioacetals were first prepared by Emil Fischer
last century, and as such, represent some of the oldest
(8) Veeneman, G. H.; Hoogerhout, P.; Westerduin, P.; Notermans,
S.; van Boom, J . H. Recl. Trav. Chim. Pays-Bas 1987, 106, 129.
(9) Zuurmond, H. M.; van der Klein, P. A. M.; Veeneman, G. H.;
van Boom, J . H. Recl. Trav. Chim. Pays-Bas 1990, 109, 437.
(10) Marino, C.; Varela, O.; de Lederkremer, R. M. Carbohydr. Res.
1989, 190, 65.
(14) Wolfrom, M. L.; Weisblat, D. I. J . Am. Chem. Soc. 1940, 62,
878.
(15) Wolfrom, M. L.; Weisblat, D. I.; Hanze, A. R. J . Am. Chem. Soc.
1940, 62, 3246.
(11) Gallo-Rodriguez, C.; Varela, O.; de Lederkremer, R. M. J . Org.
Chem. 1996, 61, 1886.
(12) Arasappan, A.; Fraser-Reid, B. Tetrahedron Lett. 1995, 36,
7967.
(16) Green, J . W. Adv. Carbohydr. Chem. Biochem. 1966, 21, 95.
(17) Wolfrom, M. L.; Weisblat, D. I.; Hanze, A. R. J . Am. Chem. Soc.
1944, 66, 2065.
(18) Farkas, I.; Menyha´rt, M.; Bogna´r, R.; Gross, H. Chem. Ber.
1965, 98, 1419.
(13) de Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547.
S0022-3263(96)01858-0 CCC: $14.00 © 1997 American Chemical Society

Furanoside Synthesis Using Acyclic Glycosyl Donors
J . Org. Chem., Vol. 62, No. 5, 1997 1235
Sch em e 2
Sch em e 3
Syn th esis of th e Glycosyl Don or s. Several methods
for the conversion of ethyl dithioacetal pentaacetates into
the corresponding 1-chloro-1-(ethylthio) derivatives have
been described, including treatment with a mixture of
known carbohydrate derivatives.19,20 Further studies
were undertaken by Pascu and Green, who demonstrated
the direct conversion of various sugar dithioacetals to
furanosides upon treatment with HgCl2 and HgO in
various aliphatic alcohols.16,21 These procedures were
later refined by Wolfrom and co-workers, who prepared
the 1-chloro-1-(ethylthio) derivatives of D-glucose and
D-galactose from the corresponding dithioacetal pentaac-
etates and demonstrated their utility as acyclic glycosyl
donors in conjunction with silver carbonate.14,15 The O,S-
acetals so formed were found to undergo a regio- and
stereoselective cyclization following deacetylation and
treatment with a mixture of HgO and HgCl2 in either
methanol or ethanol to give the corresponding â-D-
furanosides in very high yield (Scheme 1).17 Despite the
elegance of this method no attempt has since been made
to further its application.
14,15
acetyl chloride and POCl3
at reflux and dichloro-
methyl methyl ether at room temperature.17 In the
present study, it was found that a mixture of acetyl
chloride and a catalytic amount of BF3‚Et2O at reflux
resulted in a smooth conversion of the dithioacetal
pentaacetates 1-3 into the 1-chloro derivatives 4-6 over
several hours. Workup was effected simply by coevapo-
ration twice with chloroform to give the essentially pure
1-chloro-1-(ethylthio) derivatives as 1:1 mixtures of di-
astereoisomers. The D-galactose derivative 4 was recrys-
tallized before use, whereas compounds 5 and 6, derived
from D-glucose and D-mannose, respectively, were used
as syrups.
As the first part of a program22 designed to take
advantage of the potential versatility of acyclic glycosyl
donors, the suitability of the D-galactose derivative 4 for
the synthesis of â-D-galactofuranose-containing disac-
charides was examined. The targets chosen are repre-
sentative of â-D-galactofuranosides found in various
Mycobacteria species,23-25 fungi including members of the
genera Aspergillus and Penicillium,26,27 and pathogenic
protozoa such as Trypanosoma cruzi and certain Leish-
mania species.13,28,29 The application of this methodology
to D-glucose and D-mannose was also examined.
Glycosyla tion of Ca r boh yd r a te Accep tor s. Gly-
cosylation of 1,2:3,4-di-O-isopropylidene-R-D-galactose 7
with a slight excess of the D-galacto donor 4 in the
presence of a mixture of AgOTf and Ag2CO3 (1:3) in CH2-
Cl2 containing 4 Å molecular sieves at -40 °C, gave rise
to the O,S-acetal 12 in 81% yield (Scheme 3). Workup
involved the elution of the reaction mixture through a
short plug of silica with EtOAc/hexanes and was followed
by column chromatography. In a similar fashion, the
D-gluco and D-manno derivatives, 5 and 6, were treated
with the acceptor 7 to afford compounds 13 and 14 in
yields of 76% and 60%, respectively. The excellent
(19) Fischer, E. Ber. 1894, 27, 673.
(20) Wander, J . D.; Horton, D. Adv. Carbohydr. Chem. Biochem.
1976, 32, 15.
(21) Pascu, E.; Green, J . W. J . Am. Chem. Soc. 1936, 58, 1823.
(22) McAuliffe, J . C.; Hindsgaul, O. XVIIIth International Carbo-
hydrate Symposium, Milano, 1996; Abstracts of Papers, BP 169.
(23) Vilkas, E.; Amar, C.; Markovits, J .; Vliegenthart, J . F. G.;
Kamerling, J . P. Biochim. Biophys. Acta 1973, 297, 423.
(24) McNeil, M.; Wallner, S. J .; Hunter, S. W.; Brennan, P. J .
Carbohydr. Res. 1987, 166, 299.
(25) McNeil, M.; Daffe, M.; Brennan, P. J . J . Biol. Chem. 1990, 265,
18200.
1
stereoselectivity (ca. >20:1 as determined by H NMR)
of these glycosylations is likely the result of anchimeric
assistance by the neighboring 2-O-acetyl group during
the reaction, a process that would be expected to give rise
to an absolute configuration about the anomeric carbon
opposite to that at C2′ (Scheme 4).
The behavior of the D-galacto donor 4 was examined
with a variety of acceptors (7-11) (Table 1), and in all
(26) Gander, J . E.; J entoft, N. H.; Drewes, L. R.; Rick, P. D. J . Biol.
Chem. 1974, 249, 2063.
(27) Barreto-Bergter, E.; Gorin, P. A. J .; Travassos, L. R. Carbohydr.
Res. 1981, 95, 205.
(28) de Lederkremer, R. M.; Lima, C.; Ramirez, M. I.; Ferguson, M.
A. J .; Homans, S. W.; Thomas-Oates, J . J . Biol. Chem. 1991, 266,
23670.
(29) McConville, M. J .; Collidge, T. A. C.; Ferguson, M. A. J .;
Schneider, P. J . Biol. Chem. 1993, 268, 15595.

1236 J . Org. Chem., Vol. 62, No. 5, 1997
McAuliffe and Hindsgaul
Ta ble 1. Glycosyla tion w ith Acyclic Don or s
entry
donor
acceptor
product
yield (%)
1
2
3
4
5
6
7
4
5
6
4
4
4
4
7
7
7
8
9
12
13
14
15
16
17
18
81
76
60
68
82
84
71
10
11
Sch em e 4
edge, the syntheses of the â-D-galf-(1f3)-D-Mannp (T.
cruzi, Leishmania sp.),13 â-D-galf-(1f4)-L-Rhamp (Myco-
bacterium leprae, Mycobacterium tuberculosis),26 and â-D-
galf-(1f6)-D-Mannp (Aspergillus and Penicillium sp.)27
linkages have not been previously reported.
Despite the fact that these reactions were performed
in methanol, the production of mixed acetals with metha-
1
nol was estimated by H NMR to account for only a few
cases, the corresponding O,S-acetals were formed in good
to excellent yield. In a number of cases the donor 4 was
added in one portion as a solid with little difference in
the yields of product obtained.
percent of the crude products. Additional minor impuri-
ties, most likely either other ring sizes or R-D-furanosides,
were also detected in the cases of compounds 21-23. The
remarkable regio- and stereoselectivity of the cyclizations
can also be attributed to the highly favorable positioning
of O4′ with respect to the anomeric carbon in the acyclic
precursors. The cyclizations resulted predominantly in
the inversion of configuration about C1′, implicating
either an SN2 or a tight ion-pair SN1 mechanism. The
formation of 23 in 70% yield is particularly noteworthy
since it involved two simultaneous cyclizations to form a
difuranoside.
Der iva tives of D-Glu co- a n d D-Ma n n ofu r a n ose.
Treatment of compound 13 in the same fashion as for
the D-galacto analogue 12 gave the corresponding â-D-
glucofuranoside 24 (J H1′,H2′ ) 0 Hz; H4′, 4.51 ppm; C1′,
105.7 ppm)30 in 83% yield (Scheme 7, Table 2). This
method, however, was not applicable to the D-manno
compound 14 as a mixture of products was formed.
When the cyclization procedure was performed in DMF
instead, the number of impurities was reduced and
allowed the isolation of the R-D-mannofuranoside 25
(J H1′,H2′ ) 2.8 Hz; H4′, 4.49 ppm; C1′, 105.5 ppm)30 in a
yield of 40% after recrystallization.
The synthesis of partially protected O,S-acetals may
also allow access to six- and seven-membered sugars
upon cyclization, and work toward this end is currently
in progress. In addition, the application of acyclic gly-
cosyl donors to the synthesis of carbohydrate analogues
and novel macrocycles is envisioned.
Cycliza tion to â-D-ga la ctofu r a n osid es. The â-D-
galactofuranoside 19 was prepared in 86% yield by
O-deacetylation of compound 12 under Ze´mplen condi-
tions, followed by addition of HgO and HgCl2 to the
methanolic solution. TLC analysis of the reaction mix-
ture after a short time suggested the presence of a single
compound. The residue remaining upon filtration and
evaporation of the mixture was then acetylated (Ac2O/
pyridine) overnight (Scheme 5). The product obtained
following workup contained only minor impurities that
could be removed by either column chromatography or
recrystallization. The assignment of the â-D-galactofura-
nosidic structure was made on the basis of the small
coupling constant between H1′ and H2′ (<0.5 Hz) and
the chemical shifts of H4′ (4.28 ppm) and C1′ (104.9
ppm).10,30 Application of this method to D-galactosides
15-18 resulted in moderate to excellent yields of the â-D-
furanosides 20-23 (Scheme 6, Table 2). To our knowl-
Exp er im en ta l Section
Gen er a l Meth od s. TLC was performed on silica gel 60-
F254 (Merck) with detection by charring with a 10% solution
of H2SO4 in ethanol. Flash chromatography was performed
on silica gel 60 (230-400 mesh, Merck). Optical rotations were
measured at the sodium D line at 22 ( 2 oC in CHCl3. 1H NMR
spectra were recorded at 360 MHz (Bruker WM 360) or 500
(30) Cyr, N.; Perlin, A. S. Can. J . Chem. 1979, 57, 2504.

Furanoside Synthesis Using Acyclic Glycosyl Donors
J . Org. Chem., Vol. 62, No. 5, 1997 1237
Ta ble 2. Cycliza tion of O,S-Aceta ls to D-F u r a n osid es
Sch em e 5
entry
O,S-acetal
furanoside
yield (%)
1
2
3
4
5
6
7
12
15
16
17
18
13
14
19
20
21
22
23
24
25
86
89
65
74
70
83
40
Sch em e 7
Sch em e 6
[lit.14,17 mp ) 111-112 °C]; 1H NMR (360 MHz, CDCl3) δ 1.23
(t, J ) 7.5 Hz, 3H), 1.99, 2.05, 2.06, 2.07, 2.10 (5s, 15H), 2.69-
2.78 (m, 2H), 3.80 (dd, J ) 7.2, 11.7 Hz, 1H), 4.25 (dd, J ) 5.0
Hz, 1H), 5.00 (d, J ) 7.0 Hz, 1H), 5.18 (ddd, J ) 2.0 Hz, 1H),
5.20 (dd, J ) 9.7 Hz, 1H), 5.36 (dd, J ) 1.8 Hz, 1H), 5.67 (dd,
1H).
6-O-[1(S)-[2,3,4,5,6-P en ta-O-acetyl-1-(eth ylth io)-D-galac-
t it yl]]-1,2:3,4-d i-O-isop r op ylid en e-r-D-ga la ct op yr a n ose
(12). AgOTf (150 mg, 0.58 mmol) and Ag2CO3 (450 mg, 1.63
mmol) were added with stirring to a cooled (-40 °C) mixture
of the acceptor 7 (273 mg, 1.03 mmol) and powdered 4 Å
molecular sieves (500 mg) in CH2Cl2 (5 mL). After 5 min, a
solution of the donor 4 (653 mg, 1.39 mmol) in CH2Cl2 (3 mL)
was added slowly dropwise, and stirring was continued for 30
min. The mixture was then eluted (EtOAc/hexanes, 3:2)
through a short plug of silica gel to give a clear oil (740 mg)
that was further purified by flash chromatography to give 12
as a solid (577 mg, 81%): [R]D ) +14° (c 0.75); mp 131-132
1
°C (i-Pr2O); H NMR (360 MHz, CDCl3) δ 1.14 (t, J ) 7.5 Hz,
3H), 1.30, 1.31, 1.40, 1.55 (4s, 12H), 1.98, 2.00, 2.04, 2.06, 2.08
(5s, 15H), 2.42-2.62 (m, 2H), 3.20-3.24 (m, 1H), 3.79 (dd, J
) 7.3, 11.7 Hz, 1H), 3.95-4.02 (m, 2H), 4.18 (m, J ) 7.9 Hz,
1H), 4.18 (d, J ) 6.6 Hz, 1H), 4.24 (dd, J ) 4.8 Hz, 1H), 4.28
(dd, J ) 5.0, 2.5 Hz, 1H), 4.56 (dd, 1H), 5.14 (ddd, J ) 2.0 Hz,
1H), 5.19 (dd, J ) 2.0 Hz, 1H), 5.22 (dd, J ) 9.9 Hz, 1H), 5.49
(d, 1H), 5.60 (dd, 1H); 13C NMR (75 MHz) δ 14.3, 20.7, 20.9,
21.6, 24.6, 25.0, 26.0, 62.4, 66.8, 67.5, 67.9, 68.1, 68.3, 68.8,
70.4, 70.7, 71.6, 84.5, 96.4, 108.6, 109.4, 168.9, 169.9, 170.1,
170.2, 170.5. Anal. Calcd for C30H46O16S: C, 51.86; H, 6.67;
S, 4.61. Found: C, 51.78; H, 6.77; S, 4.35.
6-O-[1(S)-[2,3,4,5,6-P en ta -O-a cetyl-1-(eth ylth io)-D-glu -
cit yl]]-1,2:3,4-d i-O-isop r op ylid en e-r-D-ga la ct op yr a n ose
(13). A solution of the acceptor 7 (280 mg, 1.06 mmol) and 4
Å sieves (500 mg) in CH2Cl2 (5 mL, -30 °C) was treated with
a mixture of AgOTf and Ag2CO3 (600 mg, 1:3) followed by a
solution the crude donor 5 (690 mg, 1.4 mmol), prepared as
described above, in CH2Cl2 (2 mL) in the same fashion as for
compound 12. Filtration through a plug of silica gel (EtOAc/
hexanes, 1:1) was followed by flash chromatography to give
13 as an oil (565 mg, 76%): [R]D ) -9.6° (c 0.92); 1H NMR
(360 MHz, CDCl3) δ 1.18 (t, J ) 7.5 Hz, 3H), 1.28, 1.29, 1.39,
1.49 (4s, 12H), 1.98, 2.01, 2.04, 2.05, 2.12 (5s, 15H), 2.48-2.64
(m, 2H), 3.36-3.42 (m, 1H), 3.88-3.95 (m, 2H), 4.08 (dd, J )
5.4, 11.9 Hz, 1H), 4.16 (m, J ) 7.9 Hz, 1H), 4.23 (dd, J ) 5.2
MHz (Varian Unity 500) as indicated and referenced to either
internal CHCl3 (δ ) 7.24 ppm) or external acetone (δ ) 2.225
ppm). 13C NMR spectra were recorded at 75 MHz (Bruker AM
300) using CDCl3 (δ ) 77.1 ppm) as the reference.
Gen er a l Meth od for th e Syn th esis of Don or s 4-6. A
solution of the dithioacetal pentaacetate (1.0 g, 2.0 mmol) in
.
AcCl (4 mL) was treated with BF3 Et2O (50 µL) and held at
reflux for 4 h. The reaction mixture was then diluted with
CHCl3 (20 mL) and concentrated to give the crude 1-chloro
sulfides (5 and 6) or recrystallized (4). For 4: [R]D ) -30° (c
0.95) [lit.14,17 [R]D ) -27°]; mp 110-112 °C (i-Pr2O/CH2Cl2)

1238 J . Org. Chem., Vol. 62, No. 5, 1997
McAuliffe and Hindsgaul
Hz, 1H), 4.26 (dd, J ) 5.0, 2.4 Hz, 1H), 4.37 (d, J ) 7.6 Hz,
1H), 4.56 (dd, 1H), 5.06 (dt, J ) 5.7 Hz, 1H), 5.29 (dd, J ) 4.0
Hz, 1H), 5.38 (t, J ) 6.2 Hz, 1H), 5.45 (d, 1H), 5.54 (dd, 1H);
13C NMR (75 MHz) δ 14.5, 20.6, 20.7, 20.9, 21.9, 24.6, 25.0,
25.9, 26.0, 32.4, 61.3, 66.7, 68.1, 69.0, 69.5, 69.7, 70.2, 70.5,
70.7, 71.3, 84.5, 96.3, 108.6, 109.3, 169.4, 169.7, 169.8, 170.0,
170.5. Anal. Calcd for C30H46O16S: C, 51.86; H, 6.67; S, 4.61.
Found: C, 51.77; H, 6.40; S, 4.66.
1H), 5.55 (s, 1H), 5.83 (dd, 1H), 7.24-7.42 (m, 10H); 13C NMR
(75 MHz) δ 15.0, 20.5, 20.7, 21.0, 23.5, 54.9, 62.4, 63.8, 67.2,
67.8, 68.4, 68.9, 69.6, 71.9, 73.7, 77.8, 79.7, 85.6, 100.6, 101.3,
126.1, 127.7, 127.9, 128.3, 128.4, 129.1, 137.7, 138.3, 168.9,
169.8, 170.0, 170.4, 170.5. Anal. Calcd for C39H50O16S: C,
58.05; H, 6.24; S, 3.97. Found: C, 57.67; H, 6.26 ; S, 3.92.
Meth yl 4-O-[1(S)-[2,3,4,5,6-P en ta-O-acetyl-1-(eth ylth io)-
D-ga la ct it yl]]-2,3-O-isop r op ylid en e-r-L-r h a m n op yr a n o-
sid e (17). A solution of the acceptor 1033 (180 mg, 0.82 mmol)
and 4 Å sieves (550 mg) in CH2Cl2 (8 mL, -30 °C) was treated
with a mixture of AgOTf and Ag2CO3 (800 mg, 1:3) followed
by the donor 4 (550 mg, 1.17 mmol) in a similar fashion as for
compound 12. Filtration through a plug of silica gel (EtOAc/
hexanes, 1:2) was followed by recystallization to give 17 as
white needles (449 mg, 84%): [R]D ) +8.5° (c 1.11); mp 125.5-
6-O-[1(R)-[2,3,4,5,6-P en ta -O-a cetyl-1-(eth ylth io)-D-m a n -
n it yl]]-1,2:3,4-d i-O-isop r op ylid en e-r-D-ga la ct op yr a n ose
(14). A solution of the acceptor 7 (464 mg, 1.76 mmol) and 4
Å sieves (800 mg) in CH2Cl2 (7 mL, -40 °C) was treated with
a mixture of AgOTf and Ag2CO3 (1.0 g, 1:3) followed by a
solution the crude donor 6 (1.1 g, 2.3 mmol), prepared as
described above, in CH2Cl2 (3 mL) in the same fashion as for
compound 12. Filtration through a plug of silica gel (EtOAc/
hexanes, 1:1) was followed by flash chromatography to give
14 as a solid (740 mg, 60%): [R]D ) -37° (c 0.95); mp 115-
1
126.5 °C (i-Pr2O/hexanes); H NMR (360 MHz, CDCl3) δ 1.14
(t, J ) 7.5 Hz, 3H), 1.24-1.26 (m, 3H), 1.30, 1.50 (2s, 6H),
1.97, 2.02, 2.03, 2.06 (4s, 15H), 2.51-2.68 (m, 2H), 3.31 (s, 3H),
3.49-3.58 (m, 2H), 3.79 (dd, J ) 6.0, 12.0 Hz, 1H), 4.06 (d, J
) 5.9 Hz, 1H), 4.22 (dd, J ) 4.5 Hz, 1H), 4.27 (m, 1H), 4.78 (s,
1H), 4.83 (d, J ) 6.1 Hz, 1H), 5.17 (m, J ) 1.6 Hz, 1H), 5.18
(dd, J ) 1.4 Hz, 1H), 5.22 (dd, J ) 9.6 Hz, 1H), 5.52 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 14.1, 18.1, 20.7, 20.8, 21.0, 23.2,
26.3, 27.9, 54.9, 62.4, 64.2, 67.6, 67.9, 68.2, 69.2, 75.9, 77.0,
80.0, 83.8, 98.0, 109.2, 169.5, 169.9, 170.2, 170.5. Anal. Calcd
for C28H44O15S: C, 51.52; H, 6.79; S, 4.91. Found: C, 51.49;
H, 6.94; S, 4.69.
6-O-[1(S)-[2,3,4,5,6-P en t a -O-a cet yl-1-(et h ylt h io)-D-ga -
la ctityl]]-2,3,4,5-tetr a -O-a cetyl-1(S)-(eth ylth io)-1-O-m eth -
yl-D-ga la ctitol (18). A solution of the acceptor 1134 (177 mg,
0.417 mmol) and 4 Å sieves (260 mg) in CH2Cl2 (5 mL, -30
°C) was treated with a mixture of AgOTf and Ag2CO3 (250 mg,
1:4) followed by a solution the donor 4 (253 mg, 0.538 mmol)
in a similar fashion as for compound 12. Filtration through a
plug of silica gel (EtOAc/hexanes, 1:1) was followed by flash
1
116 °C (Et2O/hexanes); H NMR (500 MHz, CDCl3) δ 1.18 (t,
J ) 7.5 Hz, 3H), 1.28, 1.29, 1.40, 1.51 (4s, 12H), 2.02, 2.03,
2.04, 2.06 (5s, 15H), 2.51-2.63 (m, 2H), 3.53-3.58 (m, 1H),
3.93-3.98 (m, 2H), 4.07 (dd, J ) 5.3, 12.5 Hz, 1H), 4.17 (dd, J
) 2.7 Hz, 1H), 4.20 (m, J ) 7.9 Hz, 1H), 4.27 (dd, J ) 5.0, 2.3
Hz, 1H), 4.55 (dd, 1H), 4.59 (d, J ) 6.4 Hz, 1H), 5.06 (ddd, J
) 8.7 Hz, 1H), 5.28 (t, J ) 6.4 Hz, 1H), 5.47 (dd, J ) 2.0 Hz,
1H), 5.48 (d, 1H), 5.51 (dd, 1H); 13C NMR (126 MHz) δ 14.6,
20.6, 20.7, 20.8, 20.9, 23.0, 24.4, 24.9, 26.0, 61.9, 66.7, 67.0,
67.6, 68.1, 68.8, 70.5, 70.6, 70.8, 70.9, 86.1, 96.2, 108.5, 109.2,
169.5, 169.7, 169.8, 169.9, 170.6. Anal. Calcd for C30H46O16
-
S: C, 51.86; H, 6.67; S, 4.61. Found: C, 51.81; H, 6.75; S,
4.44.
Meth yl 6-O-[1(S)-[2,3,4,5,6-P en ta-O-acetyl-1-(eth ylth io)-
D-galactityl]]-2,3,4-tr i-O-ben zyl-r-D-m an n opyr an oside (15).
A solution of the acceptor 831 (327 mg, 0.70 mmol) and 4 Å
sieves (800 mg) in CH2Cl2 (6 mL, -40 °C) was treated with a
mixture of AgOTf and Ag2CO3 (600 mg, 1:3) followed by a
solution of the donor 4 (452 mg, 0.96 mmol) in CH2Cl2 (3 mL)
in the same fashion as for compound 12. Filtration through a
plug of silica gel (EtOAc/hexanes, 1:1) was followed by flash
chromatography to give 18 as an oil (255 mg, 71%): [R]D
)
+37° (c 1.58); 1H NMR (500 MHz, CDCl3) δ 1.11, 1.14 (2t, J )
7.5 Hz, 6H), 1.97, 2.04, 2.05, 2.06, 2.08, 2.10 (6s, 27H), 2.37-
2.51 (m, 4H), 3.17 (dd, J ) 10.0, 4.9 Hz, 1H), 3.30 (s, 3H), 3.67
(dd, J ) 7.0 Hz, 1H), 3.78 (dd, J ) 11.7, 7.2 Hz, 1H), 4.04 (d,
J ) 8.8 Hz, 1H), 4.11 (d, J ) 8.8 Hz, 1H), 4.23 (dd, J ) 4.7 Hz,
1H), 5.05 (dd, J ) 1.7 Hz, 1H), 5.11 (dd, J ) 1.7 Hz, 1H), 5.13
(ddd, J ) 2.0 Hz, 1H), 5.15 (dd, J ) 9.9 Hz, 2H), 5.17 (ddd, J
) 2.0 Hz, 1H), 5.56 (2dd, 2H); 13C NMR (75 MHz, CDCl3) δ
14.3, 14.5, 20.6, 20.7, 20.8, 20.9, 21.5, 21.6, 56.0, 62.3, 67.3,
67.5, 67.6, 67.8, 68.0, 68.3, 68.6, 68.7, 84.2, 85.9. Anal. Calcd
for C35H54O20S2: C, 48.94; H, 6.34; S, 7.46. Found: C, 48.99;
H, 6.46; S, 7.45.
chromatography to give 15 as an oil (431 mg, 68%): [R]D
)
1
+46° (c 0.82); H NMR (360 MHz, CDCl3) δ 1.16 (t, J ) 7.5
Hz, 3H), 1.92, 1.99, 2.02, 2.06, 2.09 (5s, 15H), 2.46-2.63 (m,
2H), 3.32 (s, 3H), 3.53 (bd, J ) 10.2 Hz, 1H), 3.68-3.78 (m,
2H), 3.74 (dd, J ) 1.7, 3.1 Hz, 1H), 3.81 (dd, J ) 7.2, 11.7 Hz,
1H), 3.88 (dd, J ) 8.4 Hz, 1H), 3.93 (dd, J ) 6.7 Hz, 1H), 4.25
(dd, J ) 4.9 Hz, 1H), 4.35 (dd, J ) 7.8 Hz, 1H), 4.64 (d, J )
1.7 Hz, 1H), 4.56-4.94 (m, 6H), 5.16 (ddd, J ) 2.0 Hz, 1H),
5.19 (dd, J ) 1.8 Hz, 1H), 5.22 (dd, J ) 9.8 Hz, 1H), 5.64 (dd,
1H), 7.16-7.36 (m, 15H); 13C NMR (75 MHz) δ 14.4, 20.5, 20.7,
20.8, 21.0, 22.6, 54.7, 62.4, 67.3, 67.9, 68.2, 68.8, 69.4, 71.0,
72.1, 72.7, 74.6, 74.8, 75.3, 80.2, 85.5, 98.8, 127.6, 127.7, 127.8,
127.9, 128.3, 128.4, 138.3, 138.5, 138.7, 169.1, 170.0, 170.3.
Anal. Calcd for C46H58O16S: C, 61.45; H, 6.50; S, 3.57.
Found: C 61.40; H, 6.54; S, 3.73.
6-O-(2,3,5,6-Tet r a -O-a cet yl-â-D-ga la ct ofu r a n osyl)-1,2:
3,4-d i-O-isop r op ylid en e-r-D-ga la ctop yr a n ose (19). The
O,S-acetal 12 (214 mg, 0.308 mmol) in methanol (3 mL) was
deacetylated with a methanolic solution of NaOMe (150 µL of
1 M) over 2 h. The mixture was then cooled (5 °C), and HgO
(150 mg, 0.69 mmol) and HgCl2 (180 mg, 0.66 mmol) were
added with rapid stirring. Following a period of stirring (30
min), the mixture was filtered, a small amount of pyridine
added (150 µL), and the solvent removed to give a white
residue. This residue was dissolved in pyridine (4 mL) and
treated with Ac2O (3 mL) in the presence of DMAP (50 mg)
over 12 h. The mixture was then diluted with water and
thoroughly extracted with EtOAc. The organic extract was
washed sequentially with water, 10% aqueous CuSO4 twice,
water, and brine. Drying (Na2SO4) and concentration of this
extract gave an oil that was purified by flash chromatography
(EtOAc/hexanes, 1:1) to give compound 19 as a solid (156 mg,
86%): [R]D ) -79° (c 1.02); mp 123-4 °C (i-Pr2O/hexanes); 1H
NMR (360 MHz, CDCl3) δ 1.30, 1.31, 1.42, 1.51 (4s, 12H), 2.02,
2.04, 2.06, 2.10 (4s, 12H), 3.56 (dd, J ) 6.5, 9.8 Hz, 1H), 3.83
(dd, J ) 6.7 Hz, 1H), 3.95 (dt, J ) 1.8 Hz, 1H), 4.16 (dd, J )
7.6, 12.0 Hz, 1H), 4.22 (dd, J ) 8.0 Hz, 1H), 4.27 (dd, J ) 5.8,
3.5 Hz, 1H), 4.28 (dd, J ) 5.0, 2.4 Hz, 1H), 4.35 (dd, J ) 2.3
Hz, 1H), 4.58 (dd, 1H), 4.94 (dd, J ) 1.8, 5.8 Hz, 1H), 5.04 (d,
Meth yl 3-O-[1(S)-[2,3,4,5,6-P en ta-O-acetyl-1-(eth ylth io)-
D-galactityl]]-2-O-ben zyl-4,6-O-ben zyliden e-r-D-m an n opy-
r a n osid e (16). A solution of the acceptor 932 (252 mg, 0.677
mmol) and 4 Å sieves (750 mg) in CH2Cl2 (6 mL, -40 °C) was
treated with a mixture of AgOTf and Ag2CO3 (600 mg, 1:3)
followed by the donor 4 (450 mg, 0.95 mmol) in CH2Cl2 (3 mL)
in the same fashion as for compound 12. Filtration through a
plug of silica gel (EtOAc/hexanes, 1:2) was followed by flash
chromatography to give 16 as an oil (496 mg, 82%): [R]D
)
1
+55° (c 1.35); H NMR (360 MHz, CDCl3) δ 1.12 (t, J ) 7.5
Hz, 3H), 1.54, 1.90, 1.97, 2.06, 2.07 (5s, 15H), 2.40-2.58 (m,
2H), 3.33 (s, 3H), 3.67 (dd, J ) 1.4, 3.2 Hz, 1H), 3.77 (ddd, J
) 9.5, 4.6, 7.3 Hz, 1H), 3.78 (dd, J ) 4.8, 11.7 Hz, 1H), 3.89 (t,
J ) 10.0 Hz, 1H), 4.17 (dd, 1H), 4.25 (dd, J ) 7.3 Hz, 1H),
4.26 (t, J ) 9.9 Hz, 1H), 4.63 (dd, 1H), 4.67 (d, 1H), 4.72, 4.84
(2d, J ) 12.2 Hz, 2H), 4.93 (d, J ) 9.1 Hz, 1H), 5.10 (dd, J )
1.3 Hz, 1H), 5.10 (ddd, J ) 1.9 Hz, 1H), 5.14 (dd, J ) 9.7 Hz,
J ) 2.8 Hz, 1H), 5.07 (s, 1H), 5.38 (ddd, 1H), 5.48 (d, 1H); 13
C
(31) Contreras, R. R.; Kamerling, J . P.; Vliegenthart, J . F. G. Recl.
Trav. Chim. Pays-Bas 1991, 110, 85.
(32) Bore´n, H. B.; Garegg, P. J .; Wallin, N.-H. Acta Chem. Scand.
1972, 26, 1082.
(33) Bebault, G. M.; Dutton, G. G. S. Can. J . Chem. 1972, 50, 3373.
(34) McAuliffe, J . C.; Hindsgaul, O. Manuscript in preparation.

Furanoside Synthesis Using Acyclic Glycosyl Donors
J . Org. Chem., Vol. 62, No. 5, 1997 1239
NMR (75 MHz, CDCl3) δ 20.7, 20.8, 24.4, 24.9, 26.0, 26.1, 63.1,
2.11 (6s, 18H), 3.63 (dd, J ) 6.9, 10.2 Hz, 1H), 3.82 (dd, J )
6.1 Hz, 1H), 4.17 (dd, J ) 7.3, 11.9 Hz, 1H), 4.26 (dd, J ) 5.5,
4.0 Hz, 1H), 4.26 (dd, J ) 5.7, 3.3 Hz, 1H), 4.32 (dd, J ) 4.1
Hz, 1H), 4.90 (s, 1H), 4.95 (dd, J ) 2.0 Hz, 1H), 4.98 (dd, J )
2.0 Hz, 1H), 5.00 (d, 1H), 5.00 (s, 1H), 5.01 (d, 1H), 5.30 (dt,
1H), 5.36 (dt, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7, 20.8, 20.9,
55.1, 62.7, 65.3, 69.3, 70.0, 76.5, 79.9, 80.4, 81.0, 81.4, 105.6,
65.0, 66.5, 69.4, 70.6, 70.9, 76.6, 80.2, 81.1, 96.3, 104.9, 108.6,
109.3, 169.5, 169.9, 170.1, 170.6. Anal. Calcd for C26H38O15
C, 52.88; H, 6.48. Found: C, 53.03; H, 6.54.
:
Meth yl 6-O-(2,3,5,6-Tetr a -O-a cetyl-â-D-ga la ctofu r a n o-
syl)-2,3,4-tr i-O-ben zyl-r-D-m a n n op yr a n osid e (20). The
O,S-acetal 15 (221 mg, 0.246 mmol) was treated in the same
fashion as for compound 19 to give compound 20 (174 mg,
89%): [R]D ) -31° (c 0.48); 1H NMR (500 MHz, CDCl3) δ 1.99,
2.02, 2.06, 2.10 (4s, 12H), 3.29 (s, 3H), 3.67-3.70 (m, 1H),
3.74-3.78 (m, 2H), 3.84-3.90 (m, 3H), 4.08 (dd, J ) 7.8, 11.9
Hz, 1H), 4.33 (dd, J ) 3.8 Hz, 1H), 4.35 (dd, J ) 5.8, 3.4 Hz,
1H), 4.70 (s, 1H), 4.58-4.92 (m, 6H), 4.94 (dd, J ) 2.1 Hz,
1H), 5.09 (d, 1H), 5.11 (s, 1H), 5.38 (dt, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.6, 20.7, 20.8, 54.7, 63.1, 66.8, 69.4, 71.5, 72.1, 72.7,
74.7, 74.8, 75.0, 80.0, 80.2, 81.1, 99.0, 105.6, 127.6, 127.7, 127.9,
128.4, 129.0, 129.7, 138.2, 138.5, 169.5, 170.1, 170.6. Anal.
Calcd for C42H50O15: C, 63.47; H, 6.34. Found: C, 63.17; H,
6.71.
106.7, 169.5, 169.7, 170.0, 170.1. Anal. Calcd for C27H38O18
C, 49.85; H, 5.89. Found: C, 49.62; H, 5.52.
:
6-O-(2,3,5,6-Tetr a -O-a cetyl-â-D-glu cofu r a n osyl)-1,2:3,4-
d i-O-isop r op ylid en e-r-D-ga la ctop yr a n ose (24). The O,S-
acetal 13 (229 mg, 0.33 mmol) was treated in the same fashion
as for compound 19 to give compound 24 (182 mg, 83%): [R]D
) -52° (c 1.27); 1H NMR (360 MHz, CDCl3) δ 1.28, 1.34, 1.40,
1.49 (4s, 12H), 1.92, 1.98, 2.03, 2.05 (4s, 12H), 3.45 (dd, J )
5.9, 8.7 Hz, 1H), 3.84 (t, J ) 7.5 Hz, 1H), 3.91 (dt, J ) 1.8 Hz,
1H), 4.16 (dd, J ) 4.1, 12.4 Hz, 1H), 4.22 (dd, J ) 8.0 Hz, 1H),
4.27 (dd, J ) 5.0, 2.3 Hz, 1H), 4.51 (dd, J ) 5.4, 9.8 Hz, 1H),
4.58 (dd, 1H), 4.58 (dd, J ) 2.3 Hz, 1H), 4.99 (s, 1H), 5.00 (s,
1H), 5.26 (ddd, 1H), 5.35 (bd, 1H), 5.46 (d, 1H); 13C NMR (75
MHz, CDCl3) δ 20.6, 20.7, 20.8, 24.2, 24.9, 25.9, 26.1, 63.2,
65.8, 66.3, 68.8, 70.5, 70.6, 70.7, 71.0, 73.3, 78.3, 80.2, 96.3,
105.7, 108.7, 109.3, 169.2, 169.4, 169.6, 170.6. Anal. Calcd
for C26H38O15: C, 52.88; H, 6.48. Found: C, 52.97; H, 6.54.
Meth yl 3-O-(2,3,5,6-Tetr a -O-a cetyl-â-D-ga la ctofu r a n o-
syl)-2-O-b e n zyl-4,6-O-b e n zylid e n e -r-D-m a n n op yr a n o-
sid e (21). The O,S-acetal 16 (195 mg, 0.242 mmol) was
treated in the same fashion as for compound 19 to give
compound 21 (110 mg, 65%): [R]D ) -24° (c 1.02); mp 156-
1
158 °C (i-Pr2O/hexanes); H NMR (360 MHz, CDCl3) δ 1.89,
6-O-(2,3,5,6-Tet r a -O-a cet yl-r-D-m a n n ofu r a n osyl)-1,2:
3,4-d i-O-isop r op ylid en e-r-D-ga la ctop yr a n ose (25). The
O,S-acetal 14 (236 mg, 0.34 mmol) in methanol (6 mL) was
treated with a methanolic solution of NaOMe (100 µL of 1 M)
over 1 h. The solution was neutralized with Amberlite IRC-
50 (H+), filtered, and concentrated. The residue was dissolved
in DMF (5 mL) and was cooled to -30 °C. A mixture of HgO
(150 mg, 0.69 mmol) and HgCl2 (180 mg, 0.66 mmol) was added
with rapid stirring, and the mixture was allowed to warm to
room temperature over 1 h. The mixture was filtered and
treated with pyridine (4 mL) and Ac2O (3 mL), and the
resulting solution was stirred overnight. The solution was
processed as described for the preparation of 19 to give
compound 25 (80 mg, 40%): [R]D ) +30° (c 1.02); mp 164-
1.91, 2.06, 2.09 (4s, 12H), 3.32 (s, 3H), 3.76 (dt, J ) 8.7, 4.2,
9.9 Hz, 1H), 3.78 (dd, J ) 1.7, 4.1 Hz, 1H), 3.84 (t, J ) 9.6 Hz,
1H), 3.90 (dd, J ) 4.1, 11.9 Hz, 1H), 4.07 (dd, J ) 7.6 Hz, 1H),
4.08 (dd, J ) 10.2 Hz, 1H), 4.16 (dd, 1H), 4.23 (dd, 1H), 4.34
(dd, J ) 5.9, 3.4 Hz, 1H), 4.68 (d, 1H), 4.70, 4.83 (2s, J ) 12.2
Hz, 2H), 4.89 (bdd, J ) 1.4 Hz, 1H), 5.03 (d, 1H), 5.05 (bs,
1H), 5.27 (dt, 1H), 5.57 (s, 1H), 7.24-7.45 (m, 10H); 13C NMR
(75 MHz, CDCl3) δ 20.5, 20.6, 20.8, 54.9, 62.9, 64.2, 68.9, 69.3,
71.9, 73.9, 74.9, 76.8, 76.9, 80.1, 81.7, 100.5, 101.7, 102.3, 126.0,
127.8, 128.1, 128.2, 128.4, 129.0, 137.7, 138.1, 169.8, 170.0,
170.1, 170.4. Anal. Calcd for C35H42O15: C, 59.82; H, 6.02.
Found: C, 59.78; H, 6.00.
Meth yl 4-O-(2,3,5,6-Tetr a -O-a cetyl-â-D-ga la ctofu r a n o-
syl)-2,3-O-isopr opyliden e-r-L-r h am n opyr an oside (22). The
O,S-acetal 17 (230 mg, 0.351 mmol) was treated in the same
fashion as for compound 19 to give compound 22 (142 mg,
1
165 °C (i-Pr2O/hexanes); H NMR (360 MHz, CDCl3) δ 1.30,
1.31, 1.41, 1.51 (4s, 12H), 1.98, 2.02, 2.03, 2.04 (4s, 12H), 3.68
(dd, J ) 7.0, 10.4 Hz, 1H), 3.75 (dd, J ) 6.4 Hz, 1H), 3.95 (dt,
J ) 1.9 Hz, 1H), 4.09 (dd, J ) 5.6, 12.3 Hz, 1H), 4.20 (dd, J )
7.9 Hz, 1H), 4.29 (dd, J ) 5.0, 2.4 Hz, 1H), 4.39 (dd, J ) 4.4,
8.7 Hz, 1H), 4.55 (dd, J ) 2.3 Hz, 1H), 4.58 (dd, 1H), 5.13 (d,
J ) 2.8 Hz, 1H), 5.21 (dd, J ) 5.1 Hz, 1H), 5.24 (ddd, 1H),
5.48 (d, 1H), 5.55 (t, 1H); 13C NMR (75 MHz, CDCl3) δ 20.3,
20.4, 20.7, 20.8, 24.5, 24.9, 26.0, 26.1, 62.9, 66.2, 67.3, 68.3,
70.6, 70.8, 75.8, 76.2, 96.3, 105.5, 108.6, 109.3, 169.3, 169.5,
169.7, 170.6. Anal. Calcd for C26H38O15: C, 52.88; H, 6.48.
Found: C, 52.77; H, 6.72.
1
74%): [R]D ) -53° (c 0.6); H NMR (360 MHz, CDCl3) δ 1.21
(d, J ) 6.2 Hz, 3H), 1.28, 1.49 (2s, 6H), 2.01, 2.03, 2.07, 2.08
(4s, 12H), 3.32 (s, 3H), 3.48 (dd, J ) 7.4, 10.0 Hz, 1H), 3.61
(dq, 1H), 4.04 (bd, J ) 5.5 Hz, 1H), 4.15 (dd, 1H), 4.16 (dd, J
) 7.2, 11.7 Hz, 1H), 4.18 (dd, J ) 5.4, 4.0 Hz, 1H), 4.27 (dd, J
) 4.9 Hz, 1H), 4.81 (bs, 1H), 4.95 (bdd, J ) 1.7 Hz, 1H), 5.03
(d, 1H), 5.33 (dt, 1H), 5.51 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 17.7, 20.6, 20.7, 20.8, 26.4, 27.9, 32.1, 54.8, 62.4, 63.8, 67.5,
69.3, 76.0, 76.4, 76.7, 78.1, 80.6, 81.1, 98.0, 103.8, 109.5, 169.5,
169.9, 170.0, 170.4. Anal. Calcd for C24H36O14: C, 52.55; H,
6.61. Found: C, 52.26; H, 6.55.
6-O-(2,3,5,6-Tetr a -O-a cetyl-â-D-ga la ctofu r a n osyl)-2,3,5-
tr i-O-a cetyl-â-D-ga la ctofu r a n osid e (23). The O,S-acetal 18
(143 mg, 0.166 mmol) was treated in the same fashion as for
compound 19 to give compound 23 (75 mg, 70%): [R]D ) -37°
Ack n ow led gm en t. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada.
1
(c 0.84); H NMR (500 MHz, CDCl3) δ 2.02, 2.06, 2.07, 2.10,
J O9618583