Sulfenate intermediates in the sulfoxide glycosylation reaction

Article abstract of DOI:10.1021/ja980827h

The sulfoxide glycosylation reaction works remarkably well for many difficult glycosylations. We attribute this in part to the fact that an extremely reactive intermediate can be generated rapidly under mild conditions at low temperature. We find that ano

Full text of DOI:10.1021/ja980827h

J. Am. Chem. Soc. 1998, 120, 5961-5969
5961
Sulfenate Intermediates in the Sulfoxide Glycosylation Reaction
Jeff Gildersleeve, Robert A. Pascal, Jr., and Daniel Kahne*
Contribution from the Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
ReceiVed March 12, 1998
Abstract: The sulfoxide glycosylation reaction works remarkably well for many difficult glycosylations. We
attribute this in part to the fact that an extremely reactive intermediate can be generated rapidly under mild
conditions at low temperature. We find that anomeric sulfenates can be formed in the reaction and that these
intermediates impede glycosylation at low temperature. A mechanism for sulfenate formation is proposed
and a strategy for minimizing sulfenate formation is presented. The energetics and reactivity of anomeric
sulfenates are also investigated. The mechanistic investigations described below have implications for other
glycosylation reactions as well.
Introduction
initially became interested in anomeric sulfoxides after noting
that they can be activated at low temperature with triflic
anhydride and that glycosylation takes place very rapidly even
with relatively unreactive nucleophiles. A simple picture of
the glycosylation reaction is shown in Scheme 1. The sulfoxide
oxygen reacts with triflic anhydride to form a sulfonium species
which ejects phenylsulfenyl triflate, producing an activated
glycosyl donor. The activated glycosyl donor is then trapped
by an alcohol to form a glycoside.
Over the past few years, however, various observations about
the glycosylation reaction have made it clear that the reaction
is much more complicated than Scheme 1 suggests. Unusual
reactivity was first noted in our original communication: the
activated sulfoxide appeared to be extremely reactive at -78
°C and yet stable at room temperature.4 We have since observed
reactions in which product starts to form at low temperature
(-78 °C), then stops forming, and then starts again after the
In a set of elegant papers published in the late 1960s, Mislow
established that allylic sulfoxides interconvert rapidly with the
corresponding allylic sulfenates through a [2,3]sigmatropic
rearrangement.1 This work explained many unusual features
of allylic sulfoxides, such as why they racemize so rapidly when
compared to other sulfoxides. It also provided a mechanistic
basis for designing new synthetic transformations, the most
important of which was the Evans method for synthesizing
allylic alcohols from allylic sulfoxides by reducing the inter-
mediate sulfenate.2 Although Mislow had shown that the
equilibrium favors the sulfoxide, the Evans reaction proceeds
to completion because reduction of the sulfenate removes it from
the equilibrium as soon as it forms.3
In this paper, we report that anomeric sulfoxides can rearrange
to anomeric sulfenates. In contrast to the allylic sulfenates
studied by Mislow and Evans, anomeric sulfenates are heavily
favored in the sulfoxide-sulfenate equilibrium. A mechanism
for sulfenate formation is proposed, and methods to minimize
sulfenate formation are developed on the basis of the proposed
mechanism.
(14) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1993, 48b, 1143.
(15) Kim, S.-H.; Augeri, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 1766.
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Tetrahedron Lett. 1994, 35, 4015.
(18) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1994, 50b, 661.
(19) Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem.
Soc. 1994, 116, 6953.
Results and Discussion
(20) Khiar, N.; Martin-Lomas, M. J. Org. Chem. 1995, 60, 7017.
(21) Wang, Y.; Zhang, H.; Voelter, W. Chem. Lett. 1995, 273.
(22) Yan, L.; Kahne, D. Synlett 1995, 523.
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(24) Alonso, I.; Martin-Lomas, M. Tetrahedron Lett. 1996, 37, 1477.
(25) Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984.
(26) Broddefalk, J.; Bergquist, K.-E.; Kihlberg, J. Tetrahedron Lett. 1996,
37, 3011.
(27) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506.
(28) Crich, D.; Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605.
(29) Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina,
K.; Horan, N.; Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still,
W. C.; Kahne, D. Science 1996, 274, 1520-1522.
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(31) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
(32) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
(33) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198.
(34) Ohnishi, Y.; Tachibana, K. Bioorg. Med. Chem. 1997, 5, 2251.
(35) Sofia, M. J.; Kakarla, R.; Kogan, N.; Dulina, R.; Hui, Y. W.;
Hatzenbuhler, N. T.; Liu, D.; Chen, A.; Wagler, T. Bioorg. Med. Chem.
Lett. 1997, 7, 2251.
For the past several years the sulfoxide glycosylation reaction
has been used to make oligosaccharides and other glycoconju-
gates both in solution and on solid phase supports.4-37 We
(1) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J.
Am. Chem. Soc. 1968, 90, 4869.
(2) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
(3) For a beautiful application combining both the Mislow rearrangement
and the Evans rearrangement, see: Miller, J. G.; Kurz, W.; Untch, K. G.;
Stork, G. J. Am. Chem. Soc. 1974, 96, 6774.
(4) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881.
(5) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9657.
(6) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.
Soc. 1992, 114, 4518.
(7) Chanteloup, L.; Beau, J.-M. Tetrahedron Lett. 1992, 33, 5347.
(8) Cheng, Y.; Ho, D. M.; Gottlieb, C. R.; Kahne, D. J. Am. Chem. Soc.
1992, 114, 7320.
(9) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 2524.
(10) Sarkar, A. K.; Matta, K. L. Carbohydr. Res. 1992, 233, 245.
(11) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087.
(12) Andreotti, A. H. J. Am. Chem. Soc. 1993, 115, 3352.
(13) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580.
(36) Zhang, H.; Wang, Y.; Thurmer, R.; Meisenbach, M.; Voelter, W.
Liebigs Ann./Recueil 1997, 1871.
(37) Crich, D.; Dai, Z. Tetrahedron Lett. 1998, 39, 1681.
S0002-7863(98)00827-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/06/1998

5962 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Scheme 1. Sulfoxide Activation and Glycosylation
GildersleeVe et al.
agent released during activation of the sulfoxide (see Scheme
3: Mechanism 1). Given the amount of sulfenate formed, this
mechanism would require an efficient pathway for lactol
formation under anhydrous conditions.
The second mechanism for sulfenate formation involves
glycosylation of unreacted sulfoxide with the activated donor
to form a sulfonium-linked disaccharide (see Scheme 3:
Mechanism 2).40 This sulfonium ion then ejects an anomeric
sulfenate and regenerates the activated donor.
Mechanism 2 provides a catalytic cycle for the interconver-
sion of sulfoxide and sulfenate. We reasoned that if such a
cycle exists, then a catalytic amount of triflic anhydride and
base should convert a diastereomerically pure sulfoxide to an
equilibrium mixture of R and â sulfenates and the four
diastereomeric sulfoxides. To probe the existence of a catalytic
cycle for the formation of sulfenate, we treated sulfoxide 1 with
a catalytic amount of triflic anhydride in the presence of base
at -78 °C. An anomeric mixture of lactols was isolated in 65%
yield along with 25% of the sulfenate 4, but no sulfoxide could
be detected.
Scheme 2. Identification of a Sulfenate
The complete consumption of sulfoxide 1 with catalytic triflic
anhydride establishes a catalytic cycle, a result which is
consistent with Mechanism 2.41 However, instead of the
expected mixture of sulfoxides and sulfenates, we isolated lactol
as the major product. Because sulfenate 4 is known to
decompose to lactol readily, it seemed possible that the lactol
isolated from the reaction mixture came from the hydrolysis of
sulfenate during work up and purification. If so, the principal
species present in the reaction mixture at low temperature would
be glycosyl sulfenate. To evaluate this possibility, we treated
sulfoxide 1 with 0.34 equiv of triflic anhydride in the presence
of base at -78 °C and monitored the 1H NMR spectrum.
Comparison with spectra of the sulfoxide starting material, the
lactols, and the pure sulfenate 4 at -78 °C indicated that all of
the sulfoxide disappeared and that the sulfenate is the major
species in the reaction mixture (see Figure 1).42
temperature has been raised. This behavior suggests that there
are different reaction pathways that must be elucidated in order
to better control the outcome of glycosylation.
One example of complex reactivity involves the reaction of
sulfoxide 1 with alcohol 2 (Scheme 2). Although all of the
sulfoxide was completely consumed at -78 °C, only a small
amount of product was formed. As the reaction was warmed
above -20 °C, more product was produced. If the reaction
was quenched at low temperature, we could isolate a small
amount of the desired disaccharide 3 (23%) along with a large
quantity of an unknown compound. The physical properties
of the unknown compound (NMR and mass spectra) suggested
that it was the anomeric sulfenate 4. This hypothesis was
confirmed by independent synthesis of the anomeric sulfenate.
Anomeric phenylsulfenates have previously been found to
decompose readily to lactols.38,39 Although some of the
sulfenate 4 formed in the course of the preceding glycosylation
reaction probably decomposed during workup and purification,
the purified yield of 4 was as high as 50% based on starting
sulfoxide. The extensive formation of sulfenate led us to
investigate how it forms and how it influences the course of
the reaction.
Possible Mechanisms for Sulfenate Formation. The con-
version of glycosyl sulfoxides to glycosyl sulfenates requires
an activating agent (triflic anhydride) and occurs at low
temperature. Therefore, we considered two mechanisms that
seem to account for these features.
The first possible mechanism for glycosyl sulfenate formation
involves the reaction of lactol present in the reaction mixture
with phenylsulfenyl triflate, a highly electrophilic sulfenylating
The experiments described above demonstrate that a catalytic
cycle for conversion of sulfoxide 1 to sulfenate 4 exists and
that this cycle is operative at -78 °C, the same temperature at
which the glycosylation reaction is initiated. Although we
cannot rule out the possibility that some sulfenate forms by
Mechanism 1, we believe that the catalytic cycle shown in
Mechanism 2 accounts for most of the sulfenate formed during
the reaction of sulfoxide 1 with glycosyl acceptor 2.
Energetics of Sulfenate Formation. An interesting implica-
tion of our mechanistic investigations is that the sulfenate 4 is
thermodynamically favored over the sulfoxide 1 under condi-
tions in which interconversion is possible. This implication was
surprising since studies on the Mislow rearrangement and related
synthetic transformations suggest that sulfoxides are usually
favored over sulfenates at equilibrium in solution. We have
compared the energetics of anomeric sulfoxides and anomeric
sulfenates to simple sulfoxides and sulfenates to try and
understand the apparent reversal in relative stabilities.
(40) Glycosylation of sulfoxides has been postulated previously, see:
Narasaka, K.; Ichikawa, Y.; Kubota, H. Chem. Lett. 1987, 2139.
(41) Crich has shown that PhSOTf can also activate sulfoxides and he
proposes the formation of PhSOSPh as a byproduct (see ref 32). Formally
another catalytic cycle exists where PhSOSPh reacts with the sulfoxide and
PhSO- is ejected. Ejection of PhSOSPh regenerates the catalyst, and PhSO-
is glycosylated to form sulfenate.
(42) The absence of methyl peaks below 1.0 ppm indicate that the other
â-sulfoxide diastereomer and the R-sulfoxide are not present in the reaction.
Small peaks at 5.25, 3.45, and 4.05 ppm are consistent with a minor amount
of lactol.
(38) The rapid decomposition to lactol can make the sulfenate difficult
to observe by TLC.
(39) Fokt, I.; Szeja, W. Carbohydr. Res. 1991, 222, 271.

Sulfenates in the Sulfoxide Glycosylation Reaction
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5963
Scheme 3. Proposed Mechanisms for Sulfenate Formation
the corresponding sulfenates in solution is likely due to the
preferential stabilization of the strong sulfoxide dipole by
interaction with solvent. Solvation overwhelms the relatively
small intrinsic preference for sulfenate and shifts the equilibrium
to favor sulfoxide.
Further calculations show, however, that an oxygen substitu-
ent on the R carbon dramatically increases the energetic
preference for sulfenate (Table 1). For example, while MeS-
OMe is favored over DMSO by 2.2 kcal/mol at the MP2/6-
31+G*//HF/6-31+G* level, MeS-OCH2OMe is favored by
12.8 kcal/mol over methoxy-DMSO. A similar effect is seen
when a fluorine is present on the R carbon (Table 1). The ability
of either oxygen or fluorine substituents on the R carbon to
increase the energetic difference between sulfoxide and sulfenate
cannot be attributed to the inductive effect of an electron-
withdrawing group because MeS-OCH2CN and MeO-SCH2-
CN are only ∼3 kcal/mol more stable than cyano-DMSO
(Table 1). Stereoelectronic stabilization of the sulfenate by
oxygen or fluorine (i.e., an anomeric effect) may largely explain
the increased energetic difference between sulfoxide and
sulfenate.
Experimental evidence in the literature supports the results
of our calculations.47,48 For example, Maricich has found that
phenyl methoxymethyl sulfoxide is quantitatively converted to
the S-phenyl O-methoxymethyl sulfenate when heated to 35 °C
for 2 days. We conclude that for compounds containing oxygen
or fluorine in the R position, the energetic difference between
sulfenate and sulfoxide is so large that favorable sulfoxide
solvation cannot overcome the intrinsic preference for the
sulfenate. Therefore, we predict that all anomeric sulfoxides
will convert to the corresponding anomeric sulfenates given a
suitable reaction pathway.
Figure 1. Low temperature NMR data.
A review of the literature confirms that sulfoxides are usually
more stable than the corresponding sulfenates in solution.43 In
one typical example, Mislow found that allyl p-tolyl sulfoxide
is favored by greater than 99% over allyl p-toluenesulfenate at
equilibrium.44 Interestingly, however, ab initio calculations by
Wolfe have indicated that sulfenates are favored over sulfoxides
in the gas phase. At the HF/6-31G*//HF/6-31G* level,45 methyl
methanesulfenate was found to be 11.3 kcal/mol more stable
than dimethyl sulfoxide.46 Our own calculations (Table 1) at
higher levels of theory indicate that the gas-phase preference
for MeS-OMe over DMSO is much less pronounced. At the
MP4/6-31+G*//MP2/6-31+G* level, MeS-OMe is calculated
to be only 3.3 kcal/mol more stable than DMSO. The
experimental observation that sulfoxides are more stable than
To test this hypothesis, we treated several structurally different
anomeric sulfoxides with catalytic triflic anhydride and base
(see Table 2). The temperature of the reaction mixtures was
increased as necessary, and the disappearance of sulfoxide was
(43) Liebman, J. F.; Crawford, K. S. K.; Slayden, S. W. In Thermo-
chemistry of Organosulphur Compounds; Liebman, J. F., Crawford, K. S.
K., Slayden, S. W., Ed.; John Wiley and Sons: Chichester, 1993; pp 217-
222.
(44) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100.
(45) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; John Wiley & Sons: New York, 1986.
(46) Wolfe, S.; Schlegel, H. B. Gazz. Chim. Ital. 1990, 120, 285.
(47) Maricich, T. J.; Harrington, C. K. J. Am. Chem. Soc. 1972, 94, 5115.
(48) Banks, M. R.; Brown, A. R.; Cameron, D. K.; Gosney, I.; Cadogan,
J. I. G. J. Chem. Soc., Perkin Trans. 2 1989, 595.

5964 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
GildersleeVe et al.
Table 1. Computational Dataa for Sulfoxides and Sulfenates
computational
level
MeS(O)CH2X
(a.u.)b
MeS-OCH2X
MeO-SCH2X
differencec
(kcal/mol)
(a.u.)b
(a.u.)b
X ) H
HF/6-31+G*//HF/6-31+G*
-551.54509
-551.55507
-552.11089
-552.12840
-552.17668
-552.13005
-552.19137
-551.56145
-551.57106
-552.11895
-552.13186
-552.18057
-552.13390
-552.19664
10.3
10.0
5.1
2.2
2.4
2.4
3.3
HF/6-31++G**//HF/6-31++G**
MP2/6-31G*//HF/6-31G*
MP2/6-31+G*//HF/6-31+G*
MP2/6-31++G**//HF/6-31++G**
MP2/6-31+G*//MP2/6-31+G*
MP4/6-31+G*//MP2/6-31+G*
X ) F
HF/6-31+G*//HF/6-31+G*
MP2/6-31+G*//HF/6-31+G*
-650.39222 (anti)d
-651.14686 (anti)
-650.42980 (gau1)d
-651.17219 (gau1)
-650.41441 (gau1)d
-651.15891 (gau1)
23.6
15.9
X ) OMe
HF/6-31+G*//HF/6-31+G*
MP2/6-31+G*//HF/6-31+G*
-665.42139 (anti)
-666.31414 (anti)
-665.45367 (gau1)
-666.33458 (gau1)
-665.44007 (gau1)
-666.32257 (gau1)
20.2
12.8
X ) CN
HF/6-31+G*//HF/6-31+G*
MP2/6-31+G*//HF/6-31+G*
-643.27284 (anti)
-644.13262 (anti)
-643.29245 (gau1)
-644.13751 (gau1)
-643.29137 (gau1)
-644.13798 (gau1)
12.3
3.4
a All but the MP4 calculations were performed by using the Spartan 4.0 package of programs (Wavefunction, Inc.), and its built-in default
thresholds for wave function and gradient convergence were employed. The MP4 single-point calculations were performed by using Gaussian94.
b 1 au ) 627.503 kcal/mol. c Difference between the sulfoxide and the most stable of the sulfenate isomers; positive values favor the sulfenate.d The
energies of only the most stable conformation of each sulfoxide or sulfenate are listed; pseudo-Newman projections of the possible conformations
are illustrated below.
Table 2. Catalytic Conversion of Sulfoxides
are significant differences in the kinetic accessibility of different
anomeric sulfenates.
Factors Influencing Sulfenate Formation. The relative
rates of several different processes presumably play a critical
role in determining the extent of sulfenate formation (Scheme
4). The starting sulfoxide can either be triflated to form the
activated species (Path A) or glycosylated to produce sulfenate
(Path B). The amount of sulfenate formed will depend on the
relative rates of triflation and sulfoxide glycosylation. As the
activated species is produced, it can react with either the alcohol
(Path C) or the sulfoxide (Path B). (In some cases, the activated
species may also react with other nucleophiles in the reaction
mixture to produce other intermediates. For example, Crich
has evidence that anomeric triflates form in some glycosylation
reactions and may be the reactive species. See below.)
Unfortunately, very little is known about the relative rates
of triflation, sulfoxide glycosylation, and alcohol glycosylation
except that they appear to depend on the structure of the starting
sulfoxide and alcohol (i.e., protecting groups, configuration of
sugar, etc.). This makes it difficult to predict whether sulfenate
formation will be a problem for any given glycosylation reaction
and also makes it difficult to control sulfenate formation by
making structural modifications.
An alternative strategy to control sulfenate formation is to
vary the order of addition of the starting materials. To suppress
sulfenate formation, we need to favor two processes: triflation
of the sulfoxide and glycosylation of the alcohol. One way to
accomplish this is to add the sulfoxide slowly to a solution of
triflic anhydride, alcohol, and base. As the sulfoxide is added,
there is a high concentration of triflic anhydride to activate the
sulfoxide and a high concentration of alcohol to trap the
activated species before more sulfoxide is added. By minimiz-
ing the amount of sulfoxide present during the addition period,
a Yields and R:â are based on purified compounds. b It appears that
two sulfenates are formed in equal amounts (based on analysis of mass
spectroscopy, crude NMR, and TLC). Only one of the compounds (14)
was stable enough to isolate and characterize. The stereochemistry of
14 was not assigned.
monitored. In every instance, the sulfoxides disappeared
completely under the catalytic activation conditions; moreover,
sulfenates were isolated in every case but one (see entry 3).49
These results confirm that anomeric sulfoxides will convert to
the corresponding sulfenates under appropriate conditions.
Nevertheless, sulfenates are not observed in every sulfoxide
glycosylation reaction. This finding, combined with the fact
that there are large differences in the temperature required to
convert anomeric sulfoxides to sulfenates, suggests that there
(49) The product in this case is a result of migration of the pivaloyl
ester to the anomeric position. While the sulfenate could not be isolated,
complete conversion of the sulfoxide under catalytic conditions could be
explained by formation of a sulfenate followed by migration of the ester.

Sulfenates in the Sulfoxide Glycosylation Reaction
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5965
Scheme 4. Potential Pathways in the Reaction
the alcohol can compete more effectively for the activated
species. We have found that even primary alcohols are not
triflated at an appreciable rate under the reaction conditions,
making this inverse addition method a viable option.
The identification of sulfenates in the reaction and the fact
that they can act as glycosyl donors at warmer temperatures
explains some unusual observations about the reaction. We
noted earlier that the sulfoxide reaction can produce glycosyl
donors that are extremely reactive at low temperatures as well
as donors that are stable at higher temperatures.53 A likely
explanation is that two different intermediates are being
observed, one that reacts at low temperature and another (a
sulfenate) that is stable until much higher temperatures.
Sulfenate formation also provides a simple explanation for the
observation that in some glycosylation reactions, only a small
amount of product is formed at low temperature even though
all of the sulfoxide is consumed. Furthermore, it explains why
raising the temperature of the reaction often results in additional
product formation, presumably through activation of the sulfenate
at higher temperatures.
Other Intermediates in the Sulfoxide Reaction. Recently,
Crich has shown that for some glycosyl donors the stereochem-
ical outcome of the sulfoxide glycosylation reaction depends
on whether the alcohol is present during the activation step.27,32
For example, premixing mannose sulfoxide 15 and an alcohol
followed by addition of triflic anhydride produces the R
glycoside, while preactivating the sulfoxide and then adding
the alcohol produces the â glycoside. The difference in
stereochemical outcome indicates that the reactions are proceed-
ing through two different intermediates. Crich has shown that
one of these intermediates is an anomeric triflate and that
reaction through the triflate leads to the â-linked product.32 He
proposes that the intermediate initially formed in the reaction
can trap an alcohol directly to form the R glycoside or can be
converted to a triflate which then reacts with an alcohol to
produce the â glycoside (see Scheme 5).
To determine how much the order of addition affects
glycoside formation, we compared three different procedures
for reacting sulfoxide 1 and acceptor 2. Each reaction was
initiated at -78 °C and quenched at -50 °C. In addition, the
number of equivalents of triflic anhydride was held constant
(1.8 equiv). Preactivation of sulfoxide 1 with triflic anhydride
followed by addition of nucleophile 2 resulted in only 26% of
disaccharide 3. When the nucleophile and sulfoxide were
premixed and then triflic anhydride was added, we obtained a
38% yield of 3. Finally, when sulfoxide 1 was added slowly
to a solution containing acceptor alcohol 2, triflic anhydride,
and base, we isolated 65% of disaccharide 3. These results
demonstrate that the order of addition can have a significant
effect on the efficiency of glycoside formation, presumably by
minimizing sulfenate formation.
Reactivity of the Sulfenate. One question that has not yet
been addressed, however, pertains to the fate of the sulfenate.
We have shown that extensive sulfenate formation impedes
glycosylation at low temperatures. We have also observed that
glycosylation reactions that stall following initiation at -78 °C
can restart at higher temperatures. This raises the possibility
that anomeric sulfenates can participate as glycosyl donors under
the reaction conditions at higher temperatures.
To address this issue, we treated purified sulfenate 4 with
nucleophile 1 in the presence of triflic anhydride and base. No
reaction was observed between -78 °C and -20 °C; however,
warming to 0 °C produced disaccharide 3 in a 50% isolated
yield. Therefore, anomeric sulfenates can act as glycosyl donors
at sufficiently high temperatures.50-52 These results also indicate
that there can be at least two pathways for glycoside formation
in the sulfoxide reaction: glycosylation at low temperature
through an activated glycosyl sulfoxide donor and glycosylation
at warmer temperatures through a glycosyl sulfenate donor.
Taken together, our studies and Crich’s studies demonstrate
that the sulfoxide reaction is very complex. At least three
different intermediates can be produced: the initially formed
reactiVe species, an anomeric triflate, and an anomeric sulfenate.
The relative proportion of each intermediate formed depends
on the structures of the glycosyl donors and acceptors as well
as on the order of addition of reagents. These intermediates
affect the outcome of a glycosylation reaction in different ways.
Thus, to achieve the desired outcome in a particular reaction, it
is important to understand what the potential intermediates are,
how they affect the reaction, and how to control the formation
(50) For the attempted use of anomeric S-O sulfenates as glycosyl
donors see Ferrier, R. J.; Furneaux, R. H.; Tyler, P. C. Carbohydr. Res.
1977, 58, 397.
(51) The exact mechanism for sulfenate activation is not clear. One
possibility is that the sulfur atom is triflated to form a Swern-like
intermediate. Gin has found that Swern intermediates are effective glycosyl
donors, see: Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc.
1997, 119, 7597.
(53) Crich has suggested that a single intermediate, an anomeric triflate,
is both highly reactive at low temperatures and stable for prolonged times
at higher temperatures (see ref 32).
(52) For the use of sulfenates as glycosyl acceptors, see: Ito, Y.; Ogawa,
T. Tetrahedron Lett. 1987, 28, 2723, 4701.

5966 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Scheme 5. Crich’s Mechanistic Proposal
GildersleeVe et al.
Analytical thin-layer chromatography (TLC) was performed using
silica gel 60 F254 precoated plates (0.25 mm thickness) with a
fluorescent indicator. Flash column chromatography was performed
using silica gel 60 (230-400 mesh) from EM Science/Bodman.
All reactions were carried out under argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions unless otherwise
noted. All reagents were purchased from commercial suppliers and
used without further purification unless otherwise noted.
of a specific intermediate in order to steer the reaction toward
the desired product.
Implications for Other Glycosylation Methods. It is
interesting to note that the order of addition can have a
significant effect with other glycosylation methods as well.
Schmidt recently reported that glycosylations of unreactive
alcohols with glycosyl imidates are more efficient with inverse
addition.54 One possible explanation is that with unreactive
alcohol acceptors, the activated species has an opportunity to
glycosylate the starting imidate. If this happened, the resulting
intermediate could break down to form the glycosyl trichloro-
acetamide, an unreactive byproduct. In fact, glycosyl trichlo-
roacetamides are frequently observed as byproducts in the
imidate reaction.55,56 Furthermore, higher proportions of the
glycosyl trichloroacetamide are observed with more unreactive
alcohol acceptors.57 These observations suggest that glycosy-
lation of unreacted glycosyl donor is not unique to the sulfoxide
reaction.
Methyl 6-O-Benzoyl-2,3-di-O-(methoxymethyl)-r-D-glucopyra-
noside (2). To a stirred solution of methyl 4-O-benzyl-2,3-di-O-
(methoxymethyl)-R-D-glucopyranoside58 (1.1 g, 2.96 mmol) in meth-
ylene chloride (10 mL) was added triethylamine (3.4 mL, 24.5 mmol)
and benzoyl chloride (1.4 mL, 12.0 mmol). The reaction was stirred
at room temperature for approximately 30 min and then diluted with
EtOAc (100 mL) and washed with 0.5 N aqueous HCl (100 mL),
saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The
aqueous layers were reextracted with EtOAc (100 mL), and the organics
were combined, dried over Na2SO4, and then concentrated in vacuo.
The crude product was taken up in ethanol (7 mL), and Pd/C-Degussa
type (100 mg) was added. The reaction was stirred under an atmosphere
of hydrogen for 12 h and then filtered through Celite and concentrated
in Vacuo. The product was purified by flash chromatography (gradient
33% to 50% EtOAc/petroleum ether) to afford 2 (0.70 g, 61%) as a
colorless oil: Rf ) 0.25 (40% EtOAc/petroleum ether); 1H NMR
(CDCl3, 270 MHz) δ 8.06 (d, J ) 7.2 Hz, 2H), 7.56 (t, J ) 7.2 Hz,
1H), 7.44 (t, J ) 7.2 Hz, 2H), 4.84 (d, J ) 3.6 Hz, 1H), 4.7-4.8 (m,
4H), 4.65 (dd, J ) 2.3, 11.9 Hz, 1H), 4.57 (dd, J ) 5.3, 11.9 Hz, 1H),
4.23 (br s, 1H), 3.91 (ddd, J ) 2.3, 5.3, 9.5 Hz, 1H), 3.71 (dd, J ) 9.5,
9.5 Hz, 1H), 3.61 (dd, J ) 3.6, 9.5 Hz, 1H), 3.50 (dd, J ) 9.5, 9.5 Hz,
1H), 3.46 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H); 13C NMR (CD3COCD3,
67.5 MHz) δ 167.0, 134.2, 131.5, 130.5, 129.7, 100.1, 98.8, 98.1, 81.0,
79.2, 71.4, 70.7, 65.2, 56.1, 55.7, 55.5; HRFABMS calcd for C18H27O9
(M + H+) 387.1655, found 387.1656.
Conclusions
The sulfoxide reaction generates a highly reactive glycosyl
donor. In hindsight, it is not surprising that this activated
glycosyl donor will glycosylate unreacted glycosyl sulfoxide.
Interception of the activated donor by the sulfoxide leads to a
much less reactive donor, an anomeric sulfenate. For many
difficult glycosylations, reaction through the highly reactive
donor is critical for the success of the glycosylation. When
sulfenate formation impedes a reaction, inverse addition can
be an effective strategy for improving the reaction.
Methyl (2,3,4-Tri-O-benzyl-r-L-fucopyranosyl)-(1-4)-6-O-benzoyl-
2,3-di-O-(methoxymethyl)-r-D-glycopyranoside (3). The combined
sulfoxide 131 (127 mg, 0.234 mmol) and 2,6-di-tert-butyl-4-methylpy-
ridine (146 mg, 0.711 mmol) were azeotroped three times with toluene
(10 mL). To the residue in methylene chloride (7 mL) was added 4 Å
molecular sieves (500 mg), and the resulting suspension was stirred at
room temperature for 1 h. The suspension was cooled to -78 °C, and
a solution of triflic anhydride (20 µL, 0.117 mmol) in methylene
chloride (300 µL) was added over 1-2 min. The reaction was warmed
to -60 °C, and then a solution of the alcohol 2 (40 mg, 0.104 mmol)
in methylene chloride (4 mL) was added dropwise via syringe. After
15 min at -60 °C, the reaction was filtered into saturated aqueous
NaHCO3 (30 mL) and extracted with methylene chloride (3 × 20 mL).
The organic layers were combined, dried over Na2SO4, and concentrated
in Vacuo. The products were purified by flash chromatography
(gradient 8-70% EtOAc/petroleum ether) to afford the disaccharide 3
(19 mg, 23%), sulfenate 4 (63 mg, 50%), and unreacted alcohol 2 (24
Experimental Section
General Methods. NMR spectra were recorded on a JEOL GSX
270 or a JEOL GSX 500 Fourier transform NMR spectrometer. Proton
chemical shifts are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) unless otherwise noted. Carbon chemical
shifts are reported in parts per million (ppm) downfield from TMS
using the solvent CD3COCD3 as an internal reference unless otherwise
noted. Coupling constants (J) are reported in hertz (Hz). Multiplicities
are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), and broadened (br). Mass spectra were obtained
on a VG ZAB, VG 7070, HP 5989A (University of California,
Riverside, Mass Spectrometry Facility), or a ZAB-SE (UIUC School
of Chemical Sciences).
(54) Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 28, 3353.
(55) Schmidt, R. R.; Effenberger, G. Carbohydr. Res. 1987, 171, 59.
(56) Nunomura, S.; Ogawa, T. Tetrahedron Lett. 1988, 29, 5681.
(57) Kobayashi, M.; Yamazaki, F.; Ito, Y.; Ogawa, T. Carbohydr. Res.
1990, 201, 51.
(58) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J. Org. Chem.
1993, 58, 6174.

Sulfenates in the Sulfoxide Glycosylation Reaction
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5967
mg, 60%). Disaccharide 3: Rf ) 0.3 (30% EtOAc/petroleum ether);
1H NMR (CDCl3, 270 MHz) δ 8.03 (d, J ) 6.9 Hz, 2H), 7.15-7.65
(m, 18 H), 5.03 (d, J ) 3.6 Hz, 1H), 4.95 (d, J ) 11.5 Hz, 1H), 4.6-
4.9 (m, 11H), 4.52 (dd, J ) 4.3,12.2 Hz, 1H), 4.25 (q, J ) 6.3 Hz,
1H), 4.07 (dd, J ) 3.6, 10.2 Hz, 1H), 3.8-4.0 (m, 3H), 3.74 (dd, J )
9.3, 9.3 Hz, 1H), 3.68 (br s, 1H), 3.53 (dd, J ) 3.6, 9.3 Hz, 1H), 3.39
(s, 3H), 3.38 (s, 3H), 3.36 (s, 3H), 1.11 (d, J ) 6.3 Hz, 3H); 13C NMR
(CD3COCD3, 67.5 MHz) δ 166.6, 140.4, 140.2, 139.8, 130.3, 129.5,
129.2, 129.1, 129.05, 129.0, 128.7, 128.4, 128.3, 128.2, 128.16, 100.0,
99.9, 99.3, 98.4, 80.5, 80.2, 79.3, 79.0, 77.2, 77.1, 75.7, 74.5, 73.0,
69.9, 68.1, 64.7, 56.6, 55.5, 55.3, 17.1; HRFABMS calcd for C45H53O13
(M - H-) 801.3486, found 801.3499. Sulfenate 4: Rf ) 0.4 (10%
EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.15-7.5 (m,
20 H), 5.01 (d, J ) 3.6 Hz, 1H), 4.96 (d, J ) 11.6 Hz, 1H), 4.87 (d,
J ) 11.6 Hz, 1H), 4.77 (t, J ) 11.3 Hz, 2H), 4.62 (d, J ) 11.6 Hz,
2H), 4.07 (dd, J ) 3.6, 10.2 Hz, 1H), 3.97 (dd, J ) 2.6, 10.2 Hz, 1H),
quenched by slow addition of H2O (10 mL) and then diluted with EtOAc
(100 mL), extracted with H2O (50 mL) and brine (50 mL), dried over
Na2SO4, and concentrated in Vacuo. The product was purified by flash
chromatography (50% methylene chloride/petroleum ether) to afford
2,6-dimethylphenyl 2,3,4-tri-O-benzyl-1-thio-â-L-fucopyranoside (3.0
1
g, 74%): Rf ) 0.3 (5% EtOAc/petroleum ether); H NMR (CDCl3,
270 MHz) δ 7.0-7.5 (m, 18H), 5.06 (d, J ) 10.5 Hz, 1H), 4.98 (d, J
) 11.9 Hz, 1H), 4.88 (d, J ) 10.5 Hz, 1H), 4.72 (m, 3H), 4.27 (d, J
) 9.6 Hz, 1H), 3.87 (dd, J ) 9.6, 9.6 Hz, 1H), 3.57 (d, J ) 2.6 Hz,
1H), 3.50 (dd, J ) 2.6, 9.6 Hz, 1H), 3.26 (q, J ) 6.3 Hz, 1H), 2.56 (s,
6H), 1.07 (d, J ) 6.3 Hz, 3H); 13C NMR (CD3COCD3, 67.5 MHz) δ
145.0, 140.3, 140.0, 139.9, 133.3, 129.7, 129.2, 129.0, 128.95, 128.9,
128.8, 128.5, 128.3, 128.25, 128.2, 90.9, 85.5, 79.5, 78.0, 76.2, 75.7,
74.7, 73.2, 22.9, 17.5; HRFABMS calcd for C35H37O4S (M - H-)
553.2413, found 553.2438.
To the above sulfide (500 mg, 0.903 mmol) in methylene chloride
(10 mL) at -42 °C was added 3-chloroperoxybenzoic acid (272 mg of
65% dispersion, 1.02 mmol). The reaction was allowed to warm to
-5 °C and then cooled to -30 °C, and dimethyl sulfide (100 µL) was
added. The reaction was diluted with methylene chloride (50 mL) and
extracted with saturated aqueous NaHCO3 (50 mL). The organic layer
was dried over Na2SO4 and concentrated in Vacuo. The products were
purified by flash chromatography (5:4:1 methylene chloride/petroleum
ether/EtOAc) to afford a mixture of 2,3,4-tri-O-benzyl-1-(2,6-dimeth-
ylphenylsulfinyl)-â-L-fucopyranosides 5 (430 mg, 84%). More polar
diastereomer: Rf ) 0.3 (5:4:1 methylene chloride/petroleum ether/
3.79 (q, J ) 6.6 Hz, 1H), 3.65 (m, 1H), 1.03 (d, J ) 6.6 Hz, 3H); 13
C
NMR (CD3COCD3, 67.5 MHz) δ 142.2, 140.7, 140.6, 140.3, 130.3,
129.7, 129.6, 129.5, 129.3, 129.2, 128.8, 128.7, 125.4, 106.9, 80.2,
79.4, 79.2, 76.3, 74.7, 73.7, 69.3, 29.6; HRDCIMS calcd for C33H38-
NO5S (M + NH4+) 560.2471, found 560.2471.
General Procedure for the Catalytic Conversion of Sulfoxides.
The combined sulfoxide (0.20 mmol) and 2,6-di-tert-butyl-4-meth-
ylpyridine (0.40 mmol) were azeotroped three times with toluene (10
mL). The residue was taken up in methylene chloride (7 mL), and 4
Å molecular sieves (500 mg) was added. The resulting suspension
was stirred at room temperature for 1 h and then cooled to -78 °C.
Forty microliters of a triflic anhydride stock solution (10 µL triflic
anhydride in 400 µL of methylene chloride; 40 µL of stock is
approximately 0.006 mmol) was added over 1 min via syringe. The
reaction was monitored by TLC and warmed if necessary until all of
the sulfoxide completely disappeared. The reaction was filtered into
saturated aqueous NaHCO3 (30 mL) and extracted with methylene
chloride (3 × 20 mL). The organic layers were combined, dried over
Na2SO4, and concentrated in Vacuo. The products were purified by
flash chromatography.
1
EtOAc); H NMR (CDCl3, 270 MHz) δ 7.1-7.5 (m, 16H), 7.01 (d, J
) 7.6 Hz, 2H), 5.09 (d, J ) 9.9 Hz, 1H), 4.99 (d, J ) 11.9 Hz, 1H),
4.87 (d, J ) 9.9 Hz, 1H), 4.70 (m, 3H), 4.35 (dd, J ) 9.1, 9.1 Hz, 1H),
3.69 (dd, J ) 2.4, 9.1 Hz, 1H), 3.59 (d, J ) 2.4 Hz, 1H), 3.44 (q, J )
6.3 Hz, 1H), 2.57 (s, 6H), 1.01 (d, J ) 6.3 Hz, 3H); 13C NMR (CD3-
COCD3, 67.5 MHz) δ 140.9, 140.7, 140.5, 140.2, 132.1, 130.8, 129.7,
129.6, 129.5, 129.3, 129.1, 129.0, 128.9, 128.7, 128.6, 94.4, 85.8, 78.3,
77.7, 76.0, 75.9, 75.7, 73.4, 20.6, 17.7; HRDCIMS calcd for C35H42-
NO5S (M + NH4+) 588.2784, found 588.2804. Less polar diastere-
omer: Rf ) 0.35 (5:4:1 methylene chloride/petroleum ether/ EtOAc);
1H NMR (CDCl3, 270 MHz) δ 7.1-7.5 (m, 18H), 6.98 (d, J ) 7.6 Hz,
2H), 5.0 (m, 3H), 4.75 (m, 3H), 4.53 (dd, J ) 9.6, 9.6 Hz, 1H), 4.06
(d, J ) 9.6 Hz, 1H), 3.68 (dd, J ) 2.6, 9.6 Hz, 1H), 3.62 (m, 1H), 3.42
(q, J ) 6.3 Hz, 1H), 2.55 (s, 6H), 1.10 (d, J ) 6.3 Hz, 3H); 13C NMR
(CD3COCD3, 67.5 MHz) δ 140.8, 140.3, 140.2, 137.2, 131.6, 131.1,
129.8, 129.6, 129.5, 129.3, 129.2, 129.1, 129.0, 128.9, 128.8, 94.4,
85.8, 78.2, 76.9, 76.5, 76.2, 75.1, 73.4, 20.4, 17.8; HRDCIMS calcd
for C35H39O5S (M + H+) 571.2518, found 571.2528.
Catalytic Conversion of 2,3,4-Tri-O-benzyl-1-(phenylsulfinyl)-
r-L-fucopyranose (1). Catalytic conversion of sulfoxide 1 afforded
25% of 2,3,4-tri-O-benzyl-1-(phenylsulfenyl)-R-L-fucopyranose (4) and
65% of an anomeric mixture of lactols.
Synthesis and Catalytic Conversion of 2,3,4-Tri-O-benzyl-1-(2,6-
dimethylphenylsulfinyl)-â-L-fucopyranoside (5a,b). To a solution
of 1,2,3,4-tetra-O-acetyl-L-fucopyranoside (7.8 g, 23.5 mmol) in
methylene chloride (60 mL) was added 2,6-dimethylthiophenol (4.7
mL, 35.3 mmol). The reaction was cooled to at -72 °C, and boron
trifluoride etherate (5.8 mL, 47.2 mmol) was added dropwise via
syringe. The reaction was warmed slowly to 0 °C and stirred at 0 °C
overnight. Saturated aqueous NaHCO3 (50 mL) was added, and the
reaction was stirred vigorously for 15 min. The organic layer was then
separated, dried over Na2SO4, and concentrated in Vacuo. The product
was purified by flash chromatography (10% acetone/petroleum ether)
to afford 2,6-dimethylphenyl 2,3,4-tri-O-acetyl-1-thio-â-L-fucopyrano-
side (7.7 g, 80%): Rf ) 0.25 (15% acetone/petroleum ether); 1H NMR
(CDCl3, 270 MHz) δ 7.13 (m, 3H), 5.31 (dd, J ) 10.2, 10.2 Hz, 1H),
5.22 (d, J ) 3.6 Hz, 1H), 4.99 (dd, J ) 3.6, 10.2 Hz, 1H), 4.38 (d, J
) 10.2 Hz, 1H), 3.62 (q, J ) 6.6 Hz, 1H), 2.55 (s, 6H), 2.20 (s, 3H),
2.13 (s, 3H), 1.99 (s, 3H), 1.14 (d, J ) 6.6 Hz, 3H); 13C NMR (CD3-
COCD3, 67.5 MHz) δ 171.6, 170.7, 170.5, 145.4, 132.9, 130.7, 129.7,
89.7, 73.8, 73.5, 71.9, 69.4, 23.2, 21.4, 21.2, 17.1; HRFABMS calcd
for C20H26O7SNa (M + Na+) 433.1297, found 433.1313.
Catalytic conversion of sulfoxide 5 afforded 66% of 2,3,4-tri-O-
benzyl-1-(2,6-dimethylphenylsulfenyl)-R-L-fucopyranose (6a), 5% of
2,3,4-tri-O-benzyl-1-(2,6-dimethylphenylsulfenyl)-â-L-fucopyranose (6b),
and 21% of an anomeric mixture of lactols. Sulfenate 6a: Rf ) 0.5
1
(10% EtOAc/petroleum ether); H NMR (CDCl3, 270 MHz) δ 7.0-
7.5 (m, 18H), 4.95 (d, J ) 3.6 Hz, 1H), 4.89 (d, J ) 11.5 Hz, 1H),
4.83 (d, J ) 11.7 Hz, 1H), 4.69 (d, J ) 11.7 Hz, 1H), 4.66 (d, J )
12.2 Hz, 1H), 4.57 (d, J ) 11.5 Hz, 1H), 4.52 (d, J ) 12.2 Hz, 1H),
3.96 (dd, J ) 3.6, 10.2 Hz, 1H), 3.80 (dd, J ) 2.4, 10.2 Hz, 1H), 3.50
(d, J ) 2.4 Hz, 1H), 3.26 (q, J ) 6.6 Hz, 1H), 2.57 (s, 6H), 0.62 (d,
J ) 6.6 Hz, 3H); 13C NMR (CD2Cl2, 67.5 MHz) δ 143.4, 139.5, 139.4,
139.2, 136.9, 131.4, 128.9, 128.8, 128.7, 128.65, 128.6, 128.3, 128.0,
104.7, 79.2, 78.8, 77.5, 75.5, 73.5, 73.4, 68.0, 22.0, 16.3; HRDCIMS
calcd for C35H42NO5S (M + NH4+) 588.2784, found 588.2795.
Sulfenate 6b: Rf ) 0.4 (10% EtOAc/petroleum ether); 1H NMR
(CDCl3, 270 MHz) δ 7.0-7.5 (m, 18H), 4.95 (d, J ) 11.5 Hz, 1H),
4.65 (m, 5H), 4.39 (d, J ) 7.6 Hz, 1H), 3.76 (dd, J ) 7.6, 9.5 Hz, 1H),
3.47 (m, 3H), 2.59 (s, 6H), 1.19 (d, J ) 6.3 Hz, 3H); 13C NMR (CD3-
COCD3, 67.5 MHz) δ 144.5, 140.8, 140.5, 137.5, 132.7, 129.6, 129.5,
129.4, 129.3, 129.1, 129.0, 128.7, 128.6, 109.2, 84.0, 81.0, 78.4, 76.2,
75,9, 73.9, 72.3, 22.6, 17.6; HRDCIMS calcd for C35H42NO5S (M +
NH4+) 588.2784, found 588.2783.
To the above sulfide (3.0 g, 7.32 mmol) in methanol (25 mL) was
added sodium methoxide (100 mg). The resulting solution was stirred
at room temperature overnight and then neutralized with Amberlite IR-
120 (plus) acidic resin. The resin was filtered and rinsed several times
with methanol (3 × 30 mL). The combined filtrate was concentrated
in Vacuo and used without further purification.
To the crude tetraol (∼7.32 mmol) in THF (20 mL) was added benzyl
bromide (5.2 mL, 43.9 mmol). The reaction was cooled to 0 °C, and
NaH (925 mg of 95% dispersion, 36.6 mmol) was added. Tetrabuty-
lammonium iodide (1.0 g) and DMF (10 mL) were added, and the
reaction was allowed to warm to room temperature. The reaction was
Catalytic Conversion of 2,3,4-Tri-O-pivaloyl-1-(phenylsulfinyl)-
r-L-fucopyranose (7). Catalytic conversion of sulfoxide 729 afforded
81% of 1,3,4-tri-O-pivaloyl-R-L-fucopyranose (8): Rf ) 0.33 (20%
1
EtOAc/petroleum ether); H NMR (CDCl3, 270 MHz) δ 6.24 (d, J )
3.6 Hz, 1H), 5.30 (d, J ) 3.3 Hz, 1H), 5.24 (dd, J ) 3.3, 10.6 Hz,

5968 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
GildersleeVe et al.
1H), 4.25 (m, 2H), 1.88 (d, J ) 8.2 Hz, 1H), 1.28 (s, 18H), 1.20 (s,
9H), 1.13 (d, J ) 6.6 Hz, 3H); 13C NMR (CD3COCD3, 67.5 MHz) δ
178.4, 178.2, 177.7, 93.8, 72.4, 72.0, 68.7, 67.0, 40.4, 40.2, 39.9, 28.1,
28.0, 27.9, 16.9; HRFABMS calcd for C21H36O8Na (M + Na+)
439.2308, found 439.2319.
7.3 Hz, 2H), 7.38 (t, J ) 7.3 Hz, 2H), 7.25 (m, 1H), 5.09 (d, J ) 3.3
Hz, 1H), 3.77 (m, 2H), 3.60 (dd, J ) 3.3, 8.9 Hz, 1H), 3.55 (s, 3H),
3.52 (s, 3H), 3.47 (m, 2H), 3.43 (s, 3H), 3.34 (s, 3H), 3.24 (dd, J )
5.3, 8.9 Hz, 1H); 13C NMR (CD3COCD3, 67.5 MHz) δ 142.2, 130.4,
128.3, 125.9, 106.8, 81.3, 80.2, 77.5, 72.1, 71.8, 61.9, 59.9, 59.7, 58.8;
HRDCIMS calcd for C16H25O6S (M + H+) 345.1372, found 345.1377.
Catalytic Conversion of 2,3,4,6-Tetra-O-benzyl-1-(phenylsulfi-
nyl)-r-D-glucopyranose (9). Catalytic conversion of sulfoxide 94
afforded 15% of 2,3,4,6-tetra-O-benzyl-1-(phenylsulfenyl)-R-D-glu-
copyranose (10) and 66% of an anomeric mixture of lactols. Sulfenate
1
Sulfenate 12b: Rf ) 0.25 (15% acetone/petroleum ether); H NMR
(CDCl3, 270 MHz) δ 7.40 (m, 4H), 7.20 (m, 1H), 4.41 (d, J ) 7.9 Hz,
1H), 3.64 (m, 2H), 3.60 (s, 3H), 3.57 (s, 3H), 3.53 (m, 1H), 3.50 (s,
3H), 3.40 (m, 2H), 3.39 (s, 3H), 3.12 (dd, J ) 3.3, 9.9 Hz, 1H);13C
NMR (CD3COCD3, 67.5 MHz) δ 142.2, 130.3, 128.1, 125.3, 110.7,
85.5, 82.8, 76.4, 75.1, 72.1, 61.7, 61.6, 59.6, 58.9; HRFABMS calcd
for C16H24O6NaS (M + Na+) 367.1191, found 367.1205.
Catalytic Conversion of 2,3-di-O-benzyl-4,6-benzylidene-1-(phe-
nylsulfinyl)-r-D-mannopyranose (13). Catalytic conversion of sul-
foxide 1333 afforded 15% of 2,3-di-O-benzyl-4,6-O-benzylidene-1-
(phenylsulfenyl)-â-D-mannopyranose (14) and 61% of an anomeric
mixture of lactols. Sulfenate 14: Rf ) 0.33 (15% acetone/petroleum
ether); 1H NMR (CDCl3, 270 MHz) δ 7.2-7.6 (m, 20H), 5.60 (s, 1H),
4.96 (d, J ) 12.0 Hz, 1H), 4.88 (d, J ) 12.0 Hz, 1H), 4.73 (d, J )
12.2 Hz, 1H), 4.59 (d, J ) 12.2 Hz, 1H), 4.57 (s, 1H), 4.34 (dd, J )
4.9, 10.5 Hz, 1H), 4.21 (dd, J ) 9.6, 9.6 Hz, 1H), 3.92 (m, 2H), 3.57
(dd, J ) 3.0, 9.6 Hz, 1H), 3.34 (ddd, J ) 4.9, 9.6, 9.6 Hz, 1H); 13C
NMR (CD3COCD3, 67.5 MHz) δ 141.8, 140.6, 140.5, 139.7, 130.5,
130.0, 129.6, 129.5, 129.4, 128.8, 128.7, 128.6, 127.7, 125.9, 108.8,
102.7, 79.8, 79.7, 79.0, 76.6, 73.4, 69.6, 69.2; HRFABMS calcd for
C33H33O6S (M + H+) 557.1998, found 557.1999.
Glycosylation Using Sulfenate (4) as the Glycosyl Donor. Sulfenate
4 (34 mg, 0.063 mmol), alcohol 2 (25 mg, 0.065 mmol), and 2,6-di-
tert-butyl-4-methylpyridine (91 mg, 0.44 mmol) were azeotroped three
times with toluene (10 mL). Methylene chloride (5 mL) was added
followed by 4 Å molecular sieves (500 mg). The resulting suspension
was stirred at room temperature for 1 h and then cooled to -78 °C. A
solution of triflic anhydride (21 µL, 0.125 mmol) in methylene chloride
(350 µL) was added over 1-2 min. The reaction was warmed slowly
and monitored by TLC for the disappearance of sulfenate 4 and the
formation of disaccharide 3. After 15 min at 0 °C, the reaction was
filtered into saturated aqueous NaHCO3 (30 mL) and extracted with
methylene chloride (3 × 20 mL). The organic layers were combined,
dried over Na2SO4, and concentrated in Vacuo. The product was
purified by flash chromatography (33% EtOAc/petroleum ether) to
afford disaccharide 3 (26 mg, 50%).
1
10: Rf ) 0.5 (10% EtOAc/petroleum ether); H NMR (CDCl3, 270
MHz) δ 7.55 (m, 2H), 7.2-7.4 (m, 21H), 7.13 (m, 2H), 5.00 (d, J )
3.6 Hz, 1H), 4.97 (d, J ) 12.2 Hz, 1H), 4.82 (d, J ) 10.9 Hz, 1H),
4.80 (d, J ) 10.9 Hz, 1H), 4.70 (d, J ) 11.9 Hz, 1H), 4.59 (m, 2H),
4.46 (d, J ) 10.9 Hz, 1H), 4.43 (d, J ) 12.2 Hz, 1H), 4.00 (dd, J )
9.2, 9.2 Hz, 1H), 4.7 (m, 3H), 3.57 (dd, J ) 3.6, 9.2 Hz, 1H), 3.39 (m,
1H); 13C NMR (CD3COCD3, 67.5 MHz) δ 141.6, 140.6, 140.2, 140.1,
139.9, 132.4, 130.4, 129.7, 129.65, 129.6, 129.3, 129.2, 129.0, 128.8,
128.7, 128.6, 126.4, 105.9, 82.8, 82.1, 79.1, 76.5, 76.1, 74.45, 74.4,
73.4, 70.0; HRFABMS calcd for C40H40O6NaS (M + Na+) 671.2443,
found 671.2456.
Synthesis and Catalytic Conversion of 2,3,4,6-Tetra-O-methyl-
1-(phenylsulfinyl)-â-D-galactopyranoside (11). To a solution of
phenyl 1-thio-â-D-galactopyranoside59 (4.0 g, 14.7 mmol) in DMF (80
mL) at 0 °C was add NaH (3.0 g of a 95% dispersion, 118 mmol).
Methyl iodide (5.5 mL, 88 mmol) was added via syringe over 5 min.
The reaction was warmed to room temperature and stirred overnight.
Methanol (5 mL) was added slowly over 15 min, and the reaction was
diluted with EtOAc (100 mL), extracted with H2O (100 mL), and brine
(100 mL), dried over Na2SO4, and concentrated in Vacuo. The product
was purified by flash chromatography (25% EtOAc/petroleum ether)
to afford of phenyl 2,3,4,5-tetra-O-methyl-1-thio-â-D-galactopyranoside
(4.0 g, 83%): Rf ) 0.3 (33% EtOAc/petroleum ether); 1H NMR (CDCl3,
270 MHz) δ 7.55 (d, J ) 7.6 Hz, 2H), 7.25 (m, 3H), 4.50 (d, J ) 9.4
Hz, 1H), 3.70 (d, J ) 3.0 Hz, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 3.45-
3.65 (m, 3H), 3.53 (s, 3H), 3.41 (dd, J ) 9.4, 9.4 Hz, 1H), 3.37 (s,
3H), 3.20 (dd, J ) 3.0, 9.4 Hz, 1H); 13C NMR (CD3COCD3, 67.5 MHz)
δ 136.6, 131.9, 130.2, 128.0, 88.4, 87.3, 80.6, 78.1, 76.7, 72.4, 61.7,
61.5, 59.7, 58.7; HRFABMS calcd for C16H24O5NaS (M + Na+)
351.1242, found 351.1239.
To the above sulfide (353 mg, 1.08 mmol) in methylene chloride
(10 mL) at -42 °C was added 3-chloroperoxybenzoic acid (314 mg of
65% dispersion, 1.18 mmol). The reaction was warmed slowly to -10
°C and then cooled to -30 °C, and dimethyl sulfide (100 µL) was
added. The reaction mixture was diluted with methylene chloride (30
mL), extracted with saturated aqueous NaHCO3 (30 mL), dried over
Na2SO4, and concentrated in Vacuo. The products were purified by
flash chromatography (25% acetone/petroleum ether) to afford a mixture
of sulfoxides 11 (319 mg, 86%). Less polar diastereomer: Rf ) 0.25
Comparison of Glycosylation Procedures. (A) Preactivation.
The combined sulfoxide 1 (82 mg, 0.151 mmol) and 2,6-di-tert-butyl-
4-methylpyridine (224 mg, 1.09 mmol) was azeotroped three times with
toluene (10 mL). To the residue in methylene chloride (5 mL) was
added 4 Å molecular sieves (500 mg), and the resulting suspension
was stirred at room temperature for 1 h. The suspension was cooled
to -78 °C, and a solution of triflic anhydride (46 µL, 0.272 mmol) in
methylene chloride (350 µL) was added over 1-2 min. A solution of
alcohol 2 (26 mg, 0.067 mmol) in methylene chloride (3 mL) was added
dropwise via syinge. The reaction was warmed to -50 °C, and after
15 min at -50 °C, the reaction was filtered into saturated aqueous
NaHCO3 (30 mL) and extracted with methylene chloride (3 × 20 mL).
The organic layers were combined, dried over Na2SO4, and concentrated
in Vacuo. The product was purified by flash chromatography (33%
EtOAc/petroleum ether) to afford disaccharide 3 (14 mg, 26%).
1
(25% acetone/petroleum ether); H NMR (CDCl3, 270 MHz) δ 7.68
(m, 2H), 7.49 (m, 3H), 4.19 (d, J ) 8.9 Hz, 1H), 3.84 (dd, J ) 8.9, 8.9
Hz, 1H), 3.65 (d, J ) 2.6 Hz, 1H), 3.56 (m, 3H), 3.50 (s, 3H), 3.48 (s,
3H), 3.46 (s, 3H), 3.37 (s, 3H), 3.30 (dd, J ) 2.6, 8.9 Hz, 1H);); 13C
NMR (CD3COCD3, 67.5 MHz) δ 144.1, 131.5, 129.9, 125.6, 98.5, 87.3,
78.9, 76.1, 75.0, 72.4, 61.6, 60.5, 59.6, 58.3; HRDCIMS calcd for
C16H25O6S (M + H+) 345.1372, found 345.1363. More polar diaste-
1
reomer: Rf ) 0.22 (25% acetone/petroleum ether); H NMR (CDCl3,
270 MHz) δ 7.63 (m, 2H), 7.48 (m, 3H), 4.01 (dd, J ) 9.5, 9.5 Hz,
1H), 3.80 (s, 3H), 3.78 (d, J ) 9.5 Hz, 1H), 3.71 (d, J ) 2.6 Hz, 1H),
3.65 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 3.40 (m, 3H), 3.27 (s, 3H);
13C NMR (CD3COCD3, 67.5 MHz) δ 142.6, 131.7, 130.0, 126.5, 94.8,
87.4, 79.7, 76.6, 76.3, 71.9, 61.8, 61.6, 59.5, 58.6; HRDCIMS calcd
for C16H25O6S (M + H+) 345.1372, found 345.1382.
Catalytic conversion of sulfoxide 11 afforded 39% of 2,3,4,6-tetra-
O-methyl-1-(phenylsulfenyl)-R-D-galactopyranose (12a), 40% of 2,3,4,6-
tetra-O-methyl-1-(phenylsulfenyl)-â-D-galactopyranose (12b), and 10%
of an anomeric mixture of lactols. Sulfenate 12a: Rf ) 0.28 (15%
acetone/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.51 (d, J )
(B) Premix. The combined sulfoxide 1 (80 mg, 0.148 mmol),
alcohol 2 (25 mg, 0.065 mmol), and 2,6-di-tert-butyl-4-methylpyridine
(223 mg, 1.09 mmol) was azeotroped three times with toluene (10 mL).
To the residue in methylene chloride (8 mL) was added 4 Å molecular
sieves (500 mg), and the resulting suspension was stirred at room
temperature for 1 h. The suspension was cooled to -78 °C, and a
solution of triflic anhydride (45 µL, 0.267 mmol) in methylene chloride
(350 µL) was added over 1-2 min. The reaction was warmed to -50
°C, and after 15 min at -50 °C, the reaction was filtered into saturated
aqueous NaHCO3 (30 mL) and extracted with methylene chloride (3
× 20 mL). The organic layers were combined, dried over Na2SO4,
and concentrated in Vacuo. The product was purified by flash
(59) Ferrier, R. J.; Furneaux, R. H. Methods in Carbohydrate Chemistry;
Academic Press: New York, 1980; Vol. VII.

Sulfenates in the Sulfoxide Glycosylation Reaction
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5969
chromatography (33% EtOAc/petroleum ether) to afford disaccharide
3 (20 mg, 38%).
Acknowledgment. This work was supported by grants from
the National Institutes of Health (to D.K.) and the National
Science Foundation (to R.A.P.), which are gratefully acknowl-
edged.
(C) Inverse Addition. The combined alcohol 2 (25 mg, 0.065
mmol) and 2,6-di-tert-butyl-4-methylpyridine (220 mg, 1.07 mmol) was
azeotroped three times with toluene (10 mL). To the residue in
methylene chloride (5 mL) was added 4 Å molecular sieves (500 mg),
and the resulting suspension was stirred at room temperature for 1 h.
The suspension was cooled to -78 °C, and a solution of triflic anhydride
(45 µL, 0.267 mmol) in methylene chloride (350 µL) was added over
1-2 min. A solution of sulfoxide 2 (80 mg, 0.148 mmol) in methylene
chloride (3 mL) was added via syringe over 10-15 min. The reaction
was warmed to -50 °C, and after 15 min at -50 °C, the reaction was
filtered into saturated aqueous NaHCO3 (30 mL) and extracted with
methylene chloride (3 × 20 mL). The organic layers were combined,
dried over Na2SO4, and concentrated in Vacuo. The product was
purified by flash chromatography (33% EtOAc/petroleum ether) to
afford disaccharide 3 (34 mg, 65%).
Supporting Information Available: 1H NMR spectra for
2-6, 8, 10-12, and 14, and low-temperature 1H NMR spectra
for the sulfoxides (both diastereomers of 1 and the R sulfoxide),
sulfenate 4, and lactols (2,3,4-tri-O-benzyl-L-fucopyranose), and
a table with the calculated energies of all conformations of
substituted sulfoxides and sulfenates examined (23 pages, print/
PDF). See any current masthead page for ordering information
and Web access instructions.
JA980827H