Chemistry of 4,6-O-benzylidene-D-glycopyranosyl triflates: Contrasting behavior between the gluco and manno series

Article abstract of DOI:10.1021/jo990243d

Activation of either anomer of S-phenyl 2,3-di-O-benzyl-4,6-O- benzylidene-1-deoxy-1-thia-D-glucopyranoside with triflic anhydride in dichloromethane at -78 °C in the presence of 2,6-di-tert-butyl-4- methylpyridine affords a highly active glycosylating species which, on addition of alcohols, provides α-glucosides with high selectivity. This selectivity stands in stark contrast to the analogous mannopyranoside series, which affords the β-mannosides with excellent selectivity under the same conditions. Low-temperature NMR experiments support the notion that a glucosyl triflate is formed in the initial activation step. Possible reasons for the diverging stereoselectivity in the gluco and manno series are discussed.

Full text of DOI:10.1021/jo990243d

4926
J . Org. Chem. 1999, 64, 4926-4930
Ch em istr y of 4,6-O-Ben zylid en e-D-glycop yr a n osyl Tr ifla tes:
Con tr a stin g Beh a vior betw een th e Glu co a n d Ma n n o Ser ies
David Crich* and Weiling Cai
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Received February 9, 1999
Activation of either anomer of S-phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia-D-glu-
copyranoside with triflic anhydride in dichloromethane at -78 °C in the presence of 2,6-di-tert-
butyl-4-methylpyridine affords a highly active glycosylating species which, on addition of alcohols,
provides R-glucosides with high selectivity. This selectivity stands in stark contrast to the analogous
mannopyranoside series, which affords the â-mannosides with excellent selectivity under the same
conditions. Low-temperature NMR experiments support the notion that a glucosyl triflate is formed
in the initial activation step. Possible reasons for the diverging stereoselectivity in the gluco and
manno series are discussed.
In tr od u ction
In a classical glycosyl strategy, involving coupling of
electrophilic and nucleophilic partners, the formation of
â-glucopyranosides is typically achieved through the use
of glucosyl donors protected by esters at the O-2 position,
which are capable of neighboring group participation.10
This requirement, which obviously does not apply to
nonclassical strategies such as the alkylation of anomeric
alkoxides11 and the opening of 1,2-anhydropyranoses as
in Danishefsky’s glycal assembly method,12,13 holds true
for all types of glycosyl donor. Indeed, in their initial
publication on the sulfoxide method, Kahne and co-
workers reported that the tetra-O-pivaloyl protected
sulfoxide 1 gave excellent â-selectivity whereas its tet-
rabenzyl counterpart 2 was moderately R-selective.5 In
the course of our work on â-mannosylation we noted the
importance of the 4,6-benzylidene protecting group. Thus,
donors 3 and 4 gave excellent yields of â-mannosides
under the typical conditions whereas 5 was much less
selective. We explained this disparity in terms of the 4,6-
benzylidene group stabilizing the intermediate R-triflate
6 with respect to formation of the oxacarbenium ion 7
whose sofa conformation imposes torsional strain on the
second ring.8,9 In reality, on the NMR time scale in CD2-
Cl2 solution at -78 °C, the oxacarbenium ions have no
observable lifetime and the effect is more one of shifting
the triflate/ion pair equilibrium so far toward the covalent
triflate that Curtin-Hammett type kinetic schemes14
going via the ion pair are not viable.8 On this basis it
seemed logical that an R-glucosyl triflate 8, with its 4,6-
benzylidene protecting group, would likewise be stabi-
lized with respect to oxacarbenium ion (9) formation and
so would permit highly selective â-glucoside formation
without the requirement for a participating ester protect-
ing group.
We have recently developed a direct method for the
formation of â-mannopyranosides. The protocol consists
of activation of 4,6-O-benzylidene-D-mannopyranosyl sul-
foxides, protected with nonparticipating groups at the 2-
and 3-positions, at low temperature in dichloromethane
solution with triflic anhydride in the presence of the
non-nucleophilic base 2,6-di-tert-butyl-4-methylpyridine
(DTBMP), followed by addition of the glycosyl acceptor.1-4
In this extension of Kahne’s sulfoxide method5-7 the key
intermediate is an R-mannosyl triflate which is displaced
SN2-wise by the nucleophile to give the â-mannoside.8 In
subsequent work we also showed that 4,6-benzylidene
protected mannosyl thioglycosides could be rapidly trans-
formed into R-mannosyl triflates by treatment with
benzenesulfenyl triflate in dichloromethane at low tem-
perature and that very high ratios of â- to R-mannosides
are then obtained on addition of the acceptor alcohol.1,2
The success of both methods depends critically on the
presence of the 4,6-benzylidene group which, we believe,8
serves to torsionally disarm9 the mannosyl triflate with
respect to formation of the R-selective oxacarbenium ion.
We reasoned that extension of this chemistry to the 4,6-
benzylidene glucopyranose series should permit the
formation of â-glucosides without the need for stereodi-
recting, participating protecting groups at the 2-position.
Here, we report that, contrary to our expectations, the
use of 2,3-di-O-benzyl-4,6-benzylidene protected glucopy-
ranosyl sulfoxides leads with excellent selectivity to the
formation of R-glucosides.
(1) Crich, D.; Sun, S. J . Am. Chem. Soc. 1998, 120, 435.
(2) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(3) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198.
(4) Crich, D.; Sun, S. J . Org. Chem. 1996, 61, 4506.
(5) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J . Am. Chem.
Soc. 1989, 111, 6881.
(6) Yan, L.; Kahne, D. J . Am. Chem. Soc. 1996, 118, 9239.
(7) Kahne and co-workers have demonstrated that an alternative
mechanism involving isomerization of the glycosyl sulfoxides to glycosyl
sulfenates is operative in some systems: Gildersleeve, J .; Pascal, R.
A.; Kahne, D. J . Am. Chem. Soc. 1998, 120, 5961.
(8) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217.
(9) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J . Org. Chem.
1996, 61, 5280.
(10) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(11) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(12) Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380.
(13) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J . Aldrichim.
Acta 1997, 30, 75.
(14) Seeman, J . I. Chem. Rev. 1983, 83, 83.
10.1021/jo990243d CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/10/1999

4,6-O-Benzylidene-D-glycopyranosyl Triflates
J . ORG. CHEM., VOL. 64, NO. 13, 1999 4927
Ta ble 1. Cou p lin g Rea ction s w ith 4,6-Ben zylid en e
P r otected Glu cosyl Don or s
donor acceptor coupling reagent product % yield R:â ratio
10
10
10
10
11
12
12
13
13
14
15
16
17
16
18
19
15
19
PhSOTf
PhSOTf
PhSOTf
PhSOTf
PhSOTf
Tf2O
Tf2O
Tf2O
Tf2O
20
21
22
23
22
24
25
24
25
98
87
70
85
80
89
72
63
65
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
1:7.5
>95:5
1:6
1
foxide 12 and DTBMP was cooled to -78 °C and its H
NMR spectrum recorded before addition of cold (-78 °C)
1
Tf2O. The H NMR spectrum, recorded within minutes
of adding the anhydride, showed complete consumption
of the sulfoxide and formation of one very major new
glucoside. This species was most easily characterized at
-78 °C by its very distinct anomeric proton resonance:
a doublet at δ 6.3 with 3J ) 3.5 Hz. In the 13C NMR
spectrum the anomeric carbon was located at δ 100.6.
By analogy with our work in the mannose series,8 and
Resu lts a n d Discu ssion
We began with the preparation of the R- and â-thio-
glucosides 10 and 11 according to literature protocols.
These were oxidized in high yields to the corresponding
sulfoxides 12 and 13. As expected on the basis of
precedent, the â-anomer gave a mixture of sulfoxides
whereas the R-anomer gave a single diastereomer, which
we assign, by analogy to the crystallographically estab-
lished mannoside series,15 as the SR epimer. This selec-
tivity arises because of the conformation imposed on the
aglyconic bond by the exo-anomeric effect and which
sterically differentiates the prochiral faces of the thiogly-
coside to a much greater extent in the axial series.15
A series of coupling reactions were carried out with
the results set out in Table 1. Contrary to our expecta-
tions, with the exception of the use of methanol as
acceptor, these reactions were extremely R-selective. This
was the case irrespective of whether the couplings were
conducted with prior low-temperature activation of a
thioglycosyl donor 10 or 11 with PhSOTf, or with a
sulfoxide donor 12 or 13, using activation by triflic
anhydride. Similarly, excellent R-selectivity was obtained
independent of the anomeric stereochemistry of the donor
employed. A further example, involving the coupling of
sulfoxide 13 to the residual hydroxyl group of allyl 3,4-
di-O-benzyl-R-L-rhamnopyranoside, appeared recently in
the literature and was reported to be completely R-selec-
tive.16 As noted, the exception to the rule involved the
use of methanol as glycosyl acceptor when moderate
â-selectivity was repeatedly obtained.
from consideration of the coupling constant, we assign
this intermediate as the R-glucosyl triflate 8. In a
continuation of this NMR experiment, the probe was
gradually warmed, with acquisition of an 1H NMR
spectrum every 10 °C until decomposition of 8 occurred.
This took place between +7 and +17 °C and led to the
relatively clean formation of a new species, identified as
the glycal 26, which was subsequently isolated in 88%
yield. Exactly analogous results were obtained for the
anomeric sulfoxide 13.
To probe the nature of the reactive intermediate in the
above glucosylation reactions, a CD2Cl2 solution of sul-
(15) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. R.;
Wink, D. J . J . Chem. Soc., Chem. Commun. 1998, 2763.
(16) Bousquet, E.; Khitri, M.; Lay, L.; Nicotra, F.; Panza, L.; Russo,
G. Carbohydr. Res. 1998, 311, 171.

4928 J . Org. Chem., Vol. 64, No. 13, 1999
Crich and Cai
Sch em e 1
that the more significant preference for the R-triflate in
the mannose series shuts off any Curtin-Hammett
kinetic scheme leading to the R-glycoside via the minor
â-triflate, whereas the reduced anomeric effect in the
glucose series permits such a scheme to operate. In this
respect we note that although the low-temperature
experiment described above indicates the preferential
formation of only one triflate, the combination of rela-
tively poor signal-to-noise ratio and resolution is such
that 5% of a second anomer would likely not be seen.
A final problem concerns the inverted selectivity
observed on the use of methanol as glycosyl acceptor.
Here, with this much smaller, less hindered nucleophile,
we can only suggest that the direct displacement of the
R-triflate is so rapid as to override any indirect â-glu-
cosidation according to Scheme 1.20 We note that Schuerch
and co-workers had previously made a related observa-
tion wherein a series of 4,6-di-O-(N-phenylcarbamoyl)-
2,3-di-O-benzylgalactopyranosyl-1R-sulfonates (especially
the triflate) gave considerably higher â-selectivity with
methanol than on coupling to other alcohols.21,22
This mode of decomposition mimics that of the R-man-
nosyl triflate 27, generated from the sulfoxide, which
decomposed to glycal 28, with the exception that the
decomposition of 27 began at the considerably lower
temperature of -10 °C. If, as we have previously sug-
gested,8 the relative decomposition temperatures of two
anomeric triflates can be taken as a measure of the
differing covalent triflate/oxacarbenium ion equilibrium
constants, then we conclude that in the glucose series
the equilibrium favors the covalent triflate even more
than in the mannose series. Clearly, this is not in accord
with any hypothesis in which the formation of the
R-glucosides observed preparatively takes place by a
Curtin-Hammett kinetic scheme with the oxacarbenium
ion 9 as the true reactive species. We therefore are led
to the conclusion that we are observing a dynamic system
in which the R-triflate (8) is in equilibrium with its less
stable but more reactive â-anomer (29) and that the rate
and equilibrium constants are such as to provide pref-
erentially the R-glucoside (Scheme 1). This type of
system, which derives its R-selectivity from the higher
reactivity of the less stable â-triflate, is by no means new.
The preferential formation of tetra-O-acetyl R-glucosides
from R-acetobromoglucose in the presence of added
bromide ion was first described by Lemieux and at-
tributed to the enhanced reactivity of the higher energy
â-bromide.17,18 Why then is such a situation not seen in
the mannose series? We suggest that the difference lies
in the R-triflate/â-triflate equilibrium constants, i.e., in
the magnitude of the anomeric effect. In effect, the
anomeric effect is larger in mannose than in glucose:
thus it was noted many years ago that whereas the
equilibration of methyl tetramethyl R- and â-glucosides
in 5% methanolic HCl gives a 3:1 R:â mixture, the
corresponding experiment in the mannose series provides
the R-methyl mannoside almost quantitatively.19 Man-
nose itself mutarotates to an approximately 69:31 R:â
mixture whereas glucose reaches equilibrium at a 37:63
R:â mixture;17 pentaacetyl R-mannopyranose is favored
over its â-anomer by 1.69 kcal.mol-1 whereas in the
glucose series the equilibrium only favors the R-anomer
Exp er im en ta l Section 23
S-P h en yl 2,3-Di-O-ben zyl-4,6-O-ben zylid en e-1-d eoxy-
1-th ia -r-D-glu cop yr a n osid e (10) a n d S-P h en yl 2,3-Di-O-
ben zyl-4,6-O-ben zylid en e-1-d eoxy-1-th ia -â-D-glu cop yr a -
n osid e (11). R-D-Glucose pentaacetate (20.0 g, 51 mmol) was
dissolved in dichloromethane (100 mL) followed by the addition
of PhSH (4.5.0 mL, 60 mmol) and SnCl4 (4.2 mL, 35 mmol).
The reaction mixture was heated to reflux under Ar overnight
before it was quenched by addition of saturated aqueous
NaHCO3 (250 mL). The aqueous layer was extracted by EtOAc
(3 × 75 mL), and the combined organic layers were washed
with brine and dried over Na2SO4. The crude product obtained
on removal of the solvent was treated with NaOH (5% aq, 50
mL) to remove the excess PhSH. A white crystalline solid (15.4
g, 68%, a 1/2 R/â mixture) was obtained by recrystallization
of the residue from EtOAc/hexane (1/10). This white crystalline
solid (15.0 g, 34.0 mmol) was dissolved in MeOH (120 mL) and
treated at room temperature with a catalytic amount of Na.
After completion (2 h, TLC), the reaction mixture was neutral-
ized by DOWEX Hx and concentrated to give the tetrahydroxyl
intermediate (9.2 g, 100%), which was further protected by
treatment with PhCH(OMe)2 (9.3 mL, 62 mmol) refluxing in
THF (100 mL) for 4 h in the presence of CSA (0.35 g, 1.0
mmol). The reaction was quenched by addition of saturated
aqueous NaHCO3 (150 mL), and the aqueous layer was
extracted by EtOAc (3 × 70 mL). The combined organic layers
were washed with brine and dried over Na2SO4, then concen-
trated. The residue obtained was recrystallized in EtOAc/
Hexane (1/10) to give S-phenyl 4,6-O-benzylidene-1-deoxy-1-
thiaglucopyranoside (6.6 g, 66%). This substance (3.6 g, 10
mmol) was further treated with NaH (2.9 g, 59.0 mmol) and
benzyl bromide (4.6 mL, 39 mmol) in THF (75 mL) at reflux
for 4 h under Ar. After addition of saturated aqueous NaHCO3,
the aqueous phase was extracted by EtOAc (3 × 30 mL) and
the combined organic layers were washed with brine, dried
over Na2SO4, and concentrated. The crude product was purified
by chromatography on silica gel, eluting with EtOAc/Hexane
(1/8), to give compounds 10 (1.6 g, 28%) and 11 (3.0 g, 56%).
10: [R]D ) -20.0 (c ) 1.4, CHCl3); 1H NMR, δ: 7.44 (m, 20H),
5.61 (d, J ) 5.2 Hz, 1H), 5.58 (s, 1H), 4.94 and 4.87 (2d, J )
11.1 Hz, 2H), 4.82 and 4.76 (2d, J ) 12.0 Hz, 2H), 4.40 (m,
by 1.10 kcal.mol-1 17
Thus it seems perfectly reasonable
.
(20) It is widely appreciated that the nucleophilicity of alcohols in
glycosylation reactions is a significant function of steric hindrance, see
refs 10 and 11.
(21) Marousek, V.; Lucas, T. J .; Wheat, P. E.; Schuerch, C. Carbo-
hydr. Res. 1978, 60, 85.
(17) Lemieux, R. U.; Morgan, A. R. Can. J . Chem. 1965, 43, 2214.
(18) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; J ames, K. J . Am.
Chem. Soc. 1975, 97, 4056.
(19) Lemieux, R. U. In Molecular Rearrangements, Part 2; De Mayo,
P., Ed.; Wiley: New York, 1964; p 709.
(22) Lucas, T. J .; Schuerch, C. Carbohydr. Res. 1975, 39, 39.
(23) For general experimental methods, see ref 2.

4,6-O-Benzylidene-D-glycopyranosyl Triflates
J . ORG. CHEM., VOL. 64, NO. 13, 1999 4929
1H), 4.20 (dd, J ) 4.9, 10.3 Hz, 1H), 3.99 (t, J ) 9.1 Hz, 1H),
3.92 (m, 1H), 3.69 (m, 2H); 13C NMR, δ: 138.8, 137.8, 137.5,
132.2, 129.2, 129.1, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8,
127.6, 126.2, 101.5, 88.0, 81.9, 79.4, 79.0, 75.5, 73.2, 68.9, 63.6.
Anal. Calcd for C33H32O5S: C, 73.31; H, 5.97; Found: C, 73.11;
H, 5.96. 11:16 1H NMR, δ: 7.45 (m, 20H), 5.60 (s, 1H), 4.94 (d,
J ) 11.1 Hz, 1H), 4.85 (m, 4H), 4.41 (dd, J ) 5.0, 12.6 Hz,
1H), 3.85 (m, 2H), 3.74 (t, J ) 9.2 Hz, 1H), 3.54 (m, 2H).
Gen er a l P r oced u r e for Oxid a tion of Th ioglycosid es
to Su lfoxid es. An aqueous solution (20 mL) of Oxone (0.62
g, 1 mmol) was added to a stirred solution of 10 or 11 (1.08 g,
2 mmol) in THF (20 mL) at 0 °C. After stirring for 3-5 h, when
TLC indicated complete consumption of the substrate, the
reaction mixture was diluted with EtOAc (30 mL), and the
aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic layers were evaporated and the residue was
purified by chromatography on silica gel eluting with EtOAc
/hexane (1:3).
1-Ad a m a n t a n yl 2,3-Di-O-b en zyl-4,6-O-b en zylid en e-r-
D-glu cop yr a n osid e (21). [R]D ) +2.6 (c ) 1.7, CHCl3); 1H
NMR, δ: 7.45 (m, 15H), 5.56 (s, 1H), 5.23 (d, J ) 3.6 Hz, 1H),
4.92 (d, J ) 11.2, 1H), 4.84 (d, J ) 11.2, 1H), 4.77 (d, J ) 12.0
Hz, 1H), 4.70 (d, J ) 12.0 Hz, 1H), 4.23 (dd, J ) 9.1, 10.2 Hz,
1H), 4.10 (m, 2H), 3.67 (t, J ) 10.2 Hz, 1H), 3.59 (t, J ) 9.3
Hz, 1H), 3.52 (dd, J ) 3.6, 9.3 Hz, 1H), 1.95 (m, 15H); 13C NMR,
δ: 139.2, 138.8, 138.7, 138.6, 137.8, 137.7, 132.5, 129.3, 128.9,
128.5, 128.4, 128.2, 128.0, 127.9, 127.6, 126.7, 126.2, 101.3,
91.2, 82.9, 79.6, 78.8, 75.4, 75.0, 73.4, 69.4, 62.2, 42.7, 36.4,
30.8. Anal. Calcd for C37H42O6‚H2O: C, 73.97; H, 7.38. Found:
C, 73.56; H, 7.21.
3-O-(2,3-Di-O-ben zyl-4,6-O-ben zylid en e-r-D-glu cop yr a -
n osyl)-1,2;5,6-di-O-isopr opyliden e-r-D-glu cofu r an ose (22).
[R]D ) +5.8 (c ) 0.8, CHCl3); 1H NMR, δ: 7.38 (m, 15H), 5.92
(d, J ) 3.6 Hz, 1H), 5.59 (s, 1H), 5.25, (d, J ) 3.6 Hz, 1H),
4.94 (d, J ) 11.4 Hz, 1H), 4.83 (d, J ) 11.4 Hz, 1H), 4.79 (s,
2H), 4.59 (d, J ) 3.6 Hz, 1H), 4.50 (m, 1H), 4.34 (dd, J ) 3.6,
9.8 Hz, 1H), 4.25 (d, J ) 2.4 Hz, 1H), 4.02 (m, 4H), 3.85 (dd,
J ) 4.5, 9.6 Hz, 1H), 3.78 (m, 2H), 3.59 (dd, J ) 4, 9.3 Hz,
1H), 1.51 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H); 13C
NMR, δ: 137, 136, 134, 129, 128, 127.8, 127.6, 125.8, 114,
108.5, 105.1, 101.0, 98.7, 84.0, 82.1, 81.1, 80.2, 79.3, 78.0, 75.1,
73.6, 72.0, 68.8, 67.0, 63.3, 27.0, 26.8, 26.3, 25.4. Anal. Calcd
for C39H46O11: C, 67.81; H, 6.71. Found: C, 67.86; H, 6.71.
N-Ben zyloxyca r b on yl-O-[2,3-d i-O-b en zyl-4,6-O-b en -
zylid en e-r-D-glu cop yr a n osyl]-L-ser in e Meth yl Ester (23).
[R]D ) +8.3 (c ) 1.2, CHCl3); 1H NMR, δ: 7.35 (m, 20H), 5.83
(d, J ) 8.4 Hz, 1H), 5.56 (s, 1H), 5.14 (s, 2H), 4.85 (m, 5H),
4.79 (d, J ) 4.5 Hz, 1H), 4.55 (m, 1H), 4.28 (dd, J ) 4.5, 9.9
Hz, 1H), 3.98 (m, 3H), 3.72 (m, 3H), 3.54 (dd, J ) 4.0, 9.3 Hz,
1H); 13C NMR, δ: 170.6, 138.9, 138.3, 137.5, 136.2, 129.0,
128.7, 128.6, 128.5, 128.4, 128.1, 127.9, 126.2, 101.4, 99.2 (1J CH
) 168.9 Hz), 82.1, 79.3, 78.4, 75.4, 73.5, 69.5, 68.9, 67.3, 63.1,
54.5, 52.8. Anal. Calcd for C39H41NO10: C, 68.51; H, 6.04; N,
2.05. Found: C, 68.68; H, 6.40; N, 1.87.
(3,3-Dim eth yl-2,4-d ioxola n yl)m eth yl 2,3-Di-O-ben zyl-
4,6-O-ben zylid en e-r-D-glu cop yr a n osid e (24). A ∼1:1 dia-
stereomeric mixture at the aglycone. 1H NMR, δ: 7.45 (m,
15H), 5.60 (d, J ) 4.1 Hz, 1H), 4.85 (m, 4H), 4.69 (dd, J ) 5.5,
12.0 Hz, 1H × 1/2,), 4.55 (t, J ) 6.7 Hz, 1H × 1/2), 4.32 (m,
2H), 4.05 (m, 2H), 3.75 (m, 7H), 3.48 (m, 2H), 1.42 (d, J ) 3.3,
3H), 1.35 (s, 3H); 13C NMR, δ: 138.6, 138.1, 137.3, 128.8, 128.3,
128.1, 127.9, 125.9, 109.4, 104.2, 101.1, 98.3, 81.9, 81.3, 79.2,
78.3, 75.2, 75.0, 74.3, 73.4, 71.3, 70.7, 66.8, 65.9, 62.5, 26.8,
25.2. Anal. Calcd for C33H38O8: C, 70.44; H, 6.80. Found: C,
69.97, H, 6.86.
Meth yl 2,3-Di-O-ben zyl-4,6-O-ben zyliden e-r-D-glu cop y-
r a n osid e (25r).24 1H NMR, δ: 7.34 (m, 15H), 5.55 (s, 1H),
4.91 and 4.69 (2d, J ) 12.0 Hz, 2H), 4.86 and 4.82 (2d, J ) 6.9
Hz, 2H), 4.60 (d, J ) 3.6 Hz, 1H), 4.26 (dd, J ) 4.5, 10. 1 Hz,
1H), 4.05 (t, J ) 9.3 Hz, 1H), 3.81 (dd, J ) 4.7, 9.9 Hz, 1H),
3.71 (t, J ) 10.2 Hz, 1H), 3.60 (t, J ) 9.3 Hz, 1H), 3.55 (dd, J
) 3.9, 9.2 Hz, 1H), 3.40 (s, 3H).
S-P h en yl 2,3-Di-O-ben zyl-4,6-O-ben zylid en e-1-d eoxy-
1-th ia -r-D-glu cop yr a n osid e Su lfoxid e (12). [R]D ) -64 (c
1
) 2.1, CHCl3); H NMR, δ: 7.45 (m, 20H), 5.50 (s, 1H), 4.81
and 4.68 (2d, J ) 10.8 Hz, 2H), 4.74 (s, 2H), 4.63 (d, J ) 3.8
Hz, 1H), 4.29 (t, J ) 4.0 Hz, 1H), 4.09 (m, 3H), 3.71 (dd, J )
7.2, 9.7 Hz, 1H), 3.47 (t, J ) 9.6 Hz, 1H); 13C NMR, δ: 142.1,
137.3, 137.1, 131.6, 129.2, 129.1, 128.6, 128.5, 128.4, 128.3,
128.1, 126.2, 125.8, 101.4, 95.0, 81.6, 78.1, 77.2, 73.7, 73.5, 69.0,
66.3. Anal. Calcd for C33H32O6S: C, 70.06; H, 5.87. Found: C,
69.53; H, 5.55.
S-P h en yl 2,3-Di-O-ben zyl-4,6-O-ben zylid en e-1-d eoxy-
1-th ia -â-D-glu cop yr a n osid e Su lfoxid e (13).16 [R]D ) -130
(c ) 1.3, CHCl3); 1H NMR, δ: 7.42 (m, 20H), 5.52 (s, 1H), 5.04
and 4.95 (2d, J ) 10.6 Hz, 2H), 4.98 and 4.82 (2d, J ) 10.5
Hz, 2H), 4.15 (t, J ) 9.2 Hz, 1H), 4.02 (dd, J ) 4.8, 11.6 Hz,
1H), 4.01 (d, J ) 9.8 Hz, 1H), 3.91 (t, J ) 9.2 Hz, 1H), 3.74 (t,
J ) 9.7 Hz, 1H), 3.28 (m, 1H); 13C NMR, δ: 139.6, 138.4, 137.7,
137.2, 131.3, 129.2, 129.1, 128.7, 128.6, 128.4, 128.3, 127.9,
126.1, 125.6, 125.3, 101.4, 93.8, 82.8, 81.3, 76.3(2), 75.1, 71.1,
68.2.
Gen er a l P r otocol for Cou p lin g w ith Su lfoxid es 12 or
13. Sulfoxide 12 or 13 (56 mg, 0.1 mmol) and DTBMP (41 mg,
0.2 mmol) were dissolved in dry dichloromethane (3 mL) under
Ar and cooled to -78 °C, followed by the rapid addition of Tf2O
(18 µL, 0.12 mmol). After 5-10 min the acceptor (0.2 mmol)
in dichloromethane (2 mL) was then added dropwise. After
stirring for a further 2-3 h, the reaction was quenched at -78
°C by adding saturated aqueous NaHCO3 (0.5 mL). The
resulting mixture was diluted with EtOAc (20 mL), dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography eluting with EtOAc/hexane (1/5) or by pre-
parative TLC.
Gen er a l P r otocol for Cou p lin g w ith Th ioglu cosid es
10 or 11. PhSCl (42 mg, 0.3 mmol) in dichloromethane (1 mL)
was added slowly to AgOTf (91 mg, 0.4 mmol) in dichlo-
romethane (2 mL) containing pulverized 3A MS (20 mg) at
-78 °C, followed by stirring for 5 min before a solution of 10
or 11 (56 mg, 0.01 mmol) and DTBMP (41 mg, 0.2 mmol) in
dichloromethane (1 mL) was added dropwise. After stirring
for 15 min, the acceptor (0.2 mmol) in dichloromethane (1 mL)
was added. After stirring for 2-3 h, the reaction was quenched
by addition of saturated aqueous NaHCO3 (1 mL) before it was
warmed to room temperature. The reaction mixture then was
diluted with EtOAc (20 mL) and was filtered over Na2SO4. The
residue obtained on removal of the solvent was purified by
chromatography column eluting with EtOAc/hexane (1/5).
Meth yl 2,3,4-Tr i-O-a cetyl-6-O-[2,3-d i-O-ben zyl-4,6-ben -
zylid en e-r-D-glu cop yr a n osyl]-r-D-glu cop yr a n osid e (20).
[R]D ) +60.8 (c ) 2.3, CHCl3); 1H NMR, δ: 7.37 (m, 15H), 5.53
(s, 1H), 5.48 (t, J ) 9.9 Hz, 1H), 4.97 (m, 4H), 4.87 (d, J ) 3.3
Hz, 1H), 4.73 (d, J ) 3.6 Hz, 1H), 4.22 (dd, J ) 3.9, 10.2 Hz,
1H), 3.95, (m, 3H), 3.68 (m, 7H), 3.37 (s, 3H), 2.07 (s, 3H), 2.06
(s, 3H), 2.02 (s, 3H); 13C NMR, δ: 170.2, 169.9, 138.8, 138.4,
137.6, 128.6, 128.4, 128.1, 127.7, 126.2, 101.4, 98.3, 96.7, 82.3,
79.2, 76.0, 75.3, 73.5, 71.1, 70.5, 69.5, 69.0, 68.3, 67.8, 62.7,
56.5, 20.8(3). Anal. Calcd for C40H46O14‚H2O: C, 62.49; H, 6.29.
Found: C, 62.65; H, 6.24.
Meth yl 2,3-Di-O-ben zyl-4,6-O-ben zylid en e-â-D-glu cop y-
r a n osid e (25â).25 1H NMR, δ: 7.36 (m, 15H), 5.58 (s, 1H),
4.86 (m, 4H), 4.43 (d, J ) 7.7 Hz, 1H), 4.37 (dd, J ) 5.1, 10.5
Hz, 1H), 3.73 (m, 3H), 3.59 (s, 3H), 3.45 (m, 2H).
Mon itor in g of th e F or m a tion a n d Decom p osition of
Tr ifla te 8 by Va r ia ble Tem p er a tu r e NMR Sp ectr oscop y.
Isola tion of 1,5-An h yd r o-4,6-O-ben zylid en e-2,3-d i-O-ben -
zyl-D-a r a bin o-h ex-1-en itol (26). The sulfoxide 12 or 13 (5.6
mg, 0.01 mmol) was mixed with DTBMP (4.5 mg, 0.02 mmol)
and dissolved in dichloromethane-d2 (0.5 mL) in an NMR tube
1
under Ar, and the H NMR spectrum was recorded at -78 °C.
Precooled Tf2O (2 µL, 0.012 mmol) was then injected at -78
°C and the tube shaken before it was reinserted into the cold
1
(-78 °C) probe. A H NMR spectrum, taken immediately, at
the same temperature showed the sulfoxide to have been
consumed in favor of one very major new substance character-
ized by a new anomeric doublet at δ 6.3 (d, J ) 3.5 Hz). In the
(24) Brimacombe, J . S. Methods Carbohydr. Chem. 1972, 6, 377.
(25) Dennison, J . C.; McGilvray, D. I. J . Chem. Soc. 1951, 1616.

4930 J . Org. Chem., Vol. 64, No. 13, 1999
Crich and Cai
13C NMR spectrum the anomeric carbon resonated at δ 100.6.
Subsequently the temperature of the probe was raised in 10
°C steps with monitoring by 1H NMR. Decomposition of the
triflate occurred between 280 and 290 K giving one very major
species, which was identified as the hexenitol 26. [R]D ) +9.3
(c ) 1.5, CHCl3); 1H NMR, δ: 7.37 (m, 15H), 6.29 (s, 1H), 5.65
(s, 1H), 4.87 (s, 2H), 4.73 (s, 2H), 4.49 (dd, J ) 0.9, 7.5 Hz),
128.4, 128.2, 127.7, 126.2, 102.6, 101.2, 80.0, 74.9, 73.6, 71.6,
69.2, 68.5, 52.4. Anal. Calcd for C27H26O5‚0.33H2O: C, 74.30;
H, 6.10. Found: C, 74.27; H, 6.26.
Ack n ow led gm en t. We thank the NIH (GM 57335)
for support of this work.
4.36 (m, 2H), 4.08 (dd, J ) 7.3, 9.9 Hz, 1H), 3.76 (m, 2H); 13
C
NMR, δ: 139.7, 138.7, 137.4, 137.1, 136.8, 129.5, 129.1, 128.6,
J O990243D