Are glycosyl triflates intermediates in the sulfoxide glycosylation method? A chemical and 1H, 13C, and 19F NMR spectroscopic investigation

Article abstract of DOI:10.1021/ja971239r

The title question is addressed by low-temperature ¹H, ¹³C, and ¹⁹F NMR spectroscopies in CD₂CL₂ as well as by the preparation of authentic samples from glycopyranosyl bromides and AgOTf. At -78°C glycosyl triflates are cleanly generated with either nonparticipating or particpating protecting groups at O-2. The glycosyl triflates identified in this manner were allowed to react with methanol, resulting in the formation of methyl glycosides. Glycosyl triflates were generated at -78°C in CD₂Cl₂ and allowed to warm gradually until decomposition was detected by ¹H and ¹⁹F NMR spectroscopy. The decomposition temperature and products are functions of the protecting groups employed.

Full text of DOI:10.1021/ja971239r

J. Am. Chem. Soc. 1997, 119, 11217-11223
11217
Are Glycosyl Triflates Intermediates in the Sulfoxide
Glycosylation Method? A Chemical and H, C, and F NMR
Spectroscopic Investigation
1
13
19
David Crich* and Sanxing Sun
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago, 845 West
Taylor Street, Room 4500, Chicago, Illinois 60607-7061
ReceiVed April 18, 1997X
1
Abstract: The title question is addressed by low-temperature H, 13C, and 19F NMR spectroscopies in CD2Cl2 as
well as by the preparation of authentic samples from glycopyranosyl bromides and AgOTf. At -78 °C glycosyl
triflates are cleanly generated with either nonparticipating or particpating protecting groups at O-2. The glycosyl
triflates identified in this manner were allowed to react with methanol, resulting in the formation of methyl glycosides.
Glycosyl triflates were generated at -78 °C in CD2Cl2 and allowed to warm gradually until decomposition was
detected by 1H and 19F NMR spectroscopy. The decomposition temperature and products are functions of the protecting
groups employed.
Introduction
approach to â-mannospyrannosides also makes use of the
sulfoxide method.19,20 Despite all of this interest no detailed
discussion of the mechanism of this reaction has yet been
published. Stimulated by an unanticipated reversal of anomeric
stereoselectivity on the coupling of the sulfoxide 1 to the
acceptor 2 in the presence of triflic anhydride (Tf2O) and 2,6-
di-tert-butyl-4-methylpyridine (DTBMP) on simple reversal of
the order of addition of the reactants to 1 (Scheme 1),21 which
we have since developed into an efficient protocol for the
stereoselective synthesis of â-mannopyranosides,22 we have
investigated the mechanism of this reaction by low-temperature
1H, 13C, and 19F NMR spectroscopies and report here on our
findings.
The use of anomeric sulfoxides as glycosyl donors has rapidly
gained a position of prominence in the field of oligosaccharide
synthesis since its introduction by Kahne in 1989. This
popularity stems from the very mild conditions and the ability
to glycosylate even the most hindered alcohols in high yield.1
The method has been successfully applied to an impressive
variety of glycosyl acceptors including acetamide, phenols and
hindered bile acids,1 hydroxylamines,2 hydroxylated amino
acids,3 tertiary alcohols,4 and a broad selection of carbohy-
drates1,5,6 by the Kahne group. Solid-phase oligosaccharide
synthesis has also been achieved through the use of glycosyl
sulfoxides by the Kahne and Still laboratories.7,8 The formation
of acyclic alkoxymethyl ethers by means of alkoxy methyl
sulfoxides has also been demonstrated by the originators of the
technique.9 Other groups have applied the sulfoxide glycosy-
lation strategy in the syntheses of complex natural products10,11
as well as in oligosaccharide12-17 and nucleoside syntheses.18
The Stork variant on the intramolecular aglycone delivery
Scheme 1
X Abstract published in AdVance ACS Abstracts, November 1, 1997.
(1) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc.
1989, 111, 6881-6882.
(2) Walker, S.; Gange, D.; Gupta, V.; Kahne, D. J. Am. Chem. Soc. 1994,
116, 3197-3206.
(3) Hamilton Andreotti, A.; Kahne, D. J. Am. Chem. Soc. 1993, 115,
3352-3353.
(4) Yan, L.; Kahne, D. Synlett 1995, 523-524.
(5) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580-1581.
(6) Yang, D.; Kim, S.-H.; Kahne, D. J. Am. Chem. Soc. 1991, 113, 4715-
4716.
(7) Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 6953-6954.
(8) 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.
(9) Silva, D. J.; Kahne, D.; Kraml, C. M. J. Am. Chem. Soc. 1994, 116,
2641-2642.
Results and Discussion
In the initial paper, Kahne and Kim reported the glucosylation
of sterically hindered secondary alcohols, phenols, and aceta-
mides with the donors 5 and 6, of undefined stereochemistry,
(10) Boeckman, R. K.; Liu, Y. J. Org. Chem. 1996, 61, 7984-7985.
(11) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 2524-
2536.
(16) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.
Soc. 1992, 114, 4518-4529.
(17) Sarkar, A. K.; Matta, K. L. Carbohydr. Res. 1992, 233, 245-250.
(18) Chanteloup, L.; Beau, J.-M. Tetrahedron Lett. 1992, 33, 5347-
5350.
(19) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088.
(20) Stork, G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248.
(21) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507.
(22) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(12) Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 1994, 35, 4015-4018.
(13) Zhang, H.; Wang, Y.; Voelter, W. Tetrahedron Lett. 1995, 36,
1243-1246.
(14) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1995, 50b, 661-
666.
(15) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1993, 48b, 1143-
1145.
S0002-7863(97)01239-0 CCC: $14.00 © 1997 American Chemical Society

11218 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Crich and Sun
Scheme 2
using Tf2O as the activator in the presence of DTBMP as the
base. These reactions were carried out in either toluene,
dichloromethane, or propionitrile by addition of the sulfoxide
to Tf2O at -78 °C, followed by addition of the acceptor and
the acid scavenger. Mixtures of R- and â-glucosides were
obtained in excellent yield. For the pivalate-protected donor
5, pure â-glucosides were obtained in all cases, which the
authors attributed to neighboring group participation. With the
perbenzyl derivative 6, the â:R ratio increased with solvent
polarity with the optimum selectivity seen in propionitrile.
Reaction times and temperatures varied widely, ranging from a
few minutes at -60 °C for hindered secondary alcohols to 12
h at room temperature for coupling to N-(trimethylsilyl)-
acetamide, prompting the authors to comment on the remarkable
stability and reactivity of the undefined, intermediate glycosyl
donor. The pattern of â-glycoside formation with donors
containing equatorial pivaloxy groups in the 2-position is a
recurring theme in subsequent papers as is the obtention of
mixtures when nonparticipating protecting groups are used. In
most subsequent papers Kahne and co-workers adhere to the
original protocol in terms of the sequence of combining the
reagents, but occasionally, as in the use of glycosyl acceptors
immobilized on a solid support,7 Tf2O is added to a preformed
mixture of the sulfoxide and the acceptor. The recent full paper
generalizing the method recommends activation of the sulfoxide
with Tf2O before addition of the glycosyl acceptor. Variations
on the theme include activation with a catalytic amount of triflic
acid5 or with trimethylsilyl triflate.12 When activation was
achieved with catalytic TfOH, methyl propiolate was used as a
sulfenic acid scavenger.5 Alcohols have sometimes been
converted to their tributylstannyl ether derivatives prior to use
as glycosyl acceptors in the sulfoxide method,23 presumably to
increase their nucleophilicity.24 Most frequently, phenyl sul-
foxides are employed, sometimes with their reactivity modified
by the incorporation of electron-donating or -withdrawing
groups,5 but as we have demonstrated through the use of ethyl
sulfoxides,25 the reaction is by no means limited to aryl
sulfoxides. Interestingly, and even frustratingly,26 Pummerer-
type chemistry is not a competing reaction in the sulfoxide
glycosylation protocol but has been noted to occur to some
extent with the acyclic sulfoxide 7.9
â-mannopyranosides, or other equatorial 1,2-cis-glycosides,
using the sulfoxide method, although it was reported in a
footnote to the original paper1 that the stereochemistry at C2
of the donor influences the stereochemical outcome. Prior to
our work25 the use of 4,6-benzylidene acetals as protecting
groups for the sulfoxide had also not been reported. The change
in stereoselectivity on going from 1 to 8 as the donor suggests
that this rigidifying system has a significant influence on the
mechanism of the reaction. The questions foremost in our minds
were therefore formulated as (i) what is the mechanism of
â-mannoside formation with donor 1; (ii) why does the
stereoselectivity of coupling to 1 change according to the
sequence of mixing the reagents; (iii) what is the nature of the
intermediate glycosyl donor, derived from 6, reactive enough
to glycosylate hindered secondary alcohols at -60 °C, yet stable
for many hours in toluene at room temperature;1 (iv) are
oxonium ions key intermediates in the glycosylation as has been
suggested;27 and (v) how does the 4,6-benzylidene protecting
group influence the stereoselectivity of mannosylation.
A working hypothesis which rationalizes the observations of
Scheme 1 is set out in Scheme 2. According to this rationale,
Tf2O serves to activate the donor 1 in the form of the sulfonium
salt 9. This collapses immediately to the oxacarbenium ion 10
and the sulfenyl triflate 11. When the activation is carried out
in the presence of the glycosyl acceptor, 10 is trapped directly,
along the axial direction for the usual stereoelectronic reasons,
to give the R-mannoside. When activation is conducted prior
to addition of the glycosyl acceptor, 10 is trapped by triflate
anion to give the R-mannosyl triflate 12. On subsequent
addition of the glycosyl acceptor 12 participates in an SN2-like
reaction with formation of the â-mannoside.
To probe this hypothesis, the simplified sulfoxide 13 was
prepared by standard means and its 1H NMR spectrum recorded
in CD2Cl2 at -78 °C in the presence of DTBMP. A 10% excess
1
of Tf2O was then added, still at -78 °C, and a new H NMR
spectrum acquired. Inspection of this spectrum revealed that
13 was transformed quantitatively, within the <5 min required
to carry out the manipulation and acquire the data, to a single
new carbohydrate species characterized by its anomeric proton
signal, a broad singlet at δ 6.20. The -78 °C 13C NMR
spectrum also indicated clean formation of a single new
carbohydrate with an anomeric carbon signal resonating at δ
104.6. An 19F NMR spectrum of the reaction mixture, still at
-78 °C, revealed a number of signals at δ 4.26, -0.037, and
-3.21. Those at δ -3.21 and 4.26 were assigned to di-tert-
butylmethylpyridinium triflate and Tf2O, respectively, with the
aid of authentic samples. Methanol was then added to the
The observation (Scheme 1) that the stereoselectivity in the
coupling of 2 to 1 could be reversed, depending on whether
Tf2O was added to activate the sulfoxide 1 before or after the
acceptor 2, first sparked our curiosity in the mechanism of this
extremely useful reaction. Our interest was heightened when
it became apparent that the closely related glycosyl donor 8
gave poor â:R ratios on coupling to simple alcohols, and this
irrespective of the mixing sequence. To our knowledge, prior
to our work, there were no previous reports of the synthesis of
1
reaction mixture, whereupon H NMR spectroscopy indicated
that the carbohydrate was consumed immediately in favor of
the formation of the methyl R- and â-mannosides 14 and 15,
respectively, in the ratio 1:7. In the 19F NMR spectrum the
resonance at δ -0.037 disappeared in favor of that at δ -3.21,
(23) Kim, S.-H.; Augeri, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 1766-1775.
(24) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.
(25) Crich, D.; Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605-
615.
(26) Crich, D.; Ritchie, T. J. Tetrahedron 1988, 44, 2319-2328.
(27) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.

Glycosyl Triflates in Sulfoxide Glycosylation
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11219
us to surmise that the powerfully electrophilic 22 itself reacts
with, and activates, the sulfoxide 13 as it is formed and in
effective competition with Tf2O. To probe this hypothesis 22,
formed in situ at -78 °C was added in CD2Cl2 to 13, whereupon
the glycosyl triflate (16) was immediately formed. This nicely
explains the absence of 22 from the reaction mixture on
treatment of 13 with Tf2O, the incomplete consumption of Tf2O
in the same experiment despite full conversion of the sulfoxide,
and the ability, noted by Kahne,5 for sulfoxide glycosylations
to be carried out in high yield with only 0.5 mol equiv of Tf2O.
We next turned our attention to the more conformationally
labile glycosyl donors 23 and 24. Treatment of sulfoxide 23
assigned to the pyridinium triflate, suggesting that the former
signal represents the true glycosyl donor and that this donor
incorporates the triflate group as an intimate structural compo-
nent, viz. the glycosyl triflate 16. On a preparative scale 14
and 15 were isolated in 9 and 53% yields, respectively, along
with 19% of the phenyl R-thiomannoside 17. In a separate
experiment, bromide 18 was treated with AgOTf and DTBMP
in CD2Cl2 under the same conditions, resulting in the formation
of a single species whose 1H NMR spectrum was identical with
that derived from treatment of the sulfoxide 13 with Tf2O. In
the 19F NMR spectrum a single signal was observed at δ -0.056,
which, given the high susceptibility of 19F NMR chemical shifts
to solvent and temperature,28 we consider to be indistinguishable
from that in the above experiment. Finally, methanol was added
to this reaction, also resulting in the immediate formation of a
1:7 mixture of 14 and 15. Thus, given the high correlation
between the 1H and 19F NMR spectra derived from the two series
of experiments, and identical outcomes on addition of methanol,
we assign the glycosyl triflate 16 as the true glycosylating
species in this 4,6-benylidene-protected system. The remote
possibility that we are observing not 16 but rather a tight ion
pair 19, which would need to be stable in CD2Cl2 on the NMR
time scale, may be excluded on chemical shift grounds. Thus,
in superacid media, the sp2 carbon in 20 and 21, simple models
for the ion pair 19, are reported to resonate at δ 248.729 and
245.5,30 respectively, whereas no 13C NMR signal was observed
with a chemical shift greater than δ 170 in the present
experiments. The large disparity between the 13C chemcal shifts
for 20 and 21 and that of the anomeric carbon noted here (δ
104.6), even taking into account the different counterions and
solvent, further suggests that any dynamic equilibrium between
the anomeric triflate 16 and the ion pair 19 very much favors
the covalently bound species.
and DTBMP in CD2Cl2 with Tf2O at -78 °C resulted in
complete conversion to single new carbohydrate characterized
1
by its anomeric resonance at δ 6.17 in the H NMR spectrum
and a signal at δ -0.033 in the 19F NMR spectrum. Attempted
characterization of this new species by 13C NMR spectroscopy
at -78 °C failed owing to decomposition over the several hours
required to acquire a spectrum with a sufficient signal-to-noise
ratio. As in the 4,6-benzylidene-protected series, benzenesulfe-
nyl triflate (22) was not identified in the reaction mixture.
Reaction of 24 with AgOTf in CD2Cl2 at -78 °C resulted in
the identical signals, so confirming the formation of the glycosyl
triflate 25 as a key intermediate in these reactions. Workup of
either NMR experiment with methanol at -78 °C resulted in
the formation of approximately 1:1 mixtures of the methyl
mannosides 26 and 27. On a slightly larger scale, treatment of
23 with Tf2O and DTBMP at low temperatures, followed by
treatment with methanol, led to the isolation of 26 and 27 in 26
and 40% yields, respectively, and of the thioglycoside 28 in
12% yield.
The assignment of anomeric stereochemistry for both 16 and
25 is based on two factors. First, the chemical shift of the
anomeric proton in both 16 and 25, at δ 6.20 and 6.17,
respectively, is most consistent with the R-glycoside. Schuerch
has previously prepared the R- and â-glucosyl toluenesulfonates
29 and 30 and finds the anomeric protons to resonate at δ 6.1
The hypothetical mechanism (Scheme 2) predicts the forma-
tion of a sulfenyl triflate in an equal amount to that of the
glycosyl triflate. To assist in identification of this species in
the 19F NMR spectrum, an authentic sample was prepared by
reaction of benzenesulfenyl chloride with silver triflate31 in CD2-
Cl2 at -78 °C in the probe of the NMR spectrometer. The 19
F
NMR spectrum consisted of a single resonance at δ -3.17,
which we therefore assign to 22. Somewhat to our surprise,
this signal did not correspond to any of those observed on
treatment of 13 with Tf2O.32 This unanticipated absense led
(28) Jameson, C. J. In Multinuclear NMR; Mason, J., Ed.; Plenum: New
York, 1987; pp 437-445.
and 5.5,33 respectively. A similar correlation is also found with
(29) Forsyth, D. A.; Osterman, V. A.; DeMember, J. R. J. Am. Chem.
Soc. 1985, 107, 818-822.
(32) In a control experiment, under similar concentration and temperature,
PhSOTf and DTBMPH+TfO- were fully resolved by 19F NMR spectros-
copy, indicating that PhSOTf is truly absent from the reaction mixture and
not simply obscured by the signal due to the pyridinium triflate.
(33) Eby, R.; Schuerch, C. Carbohydr. Res. 1974, 34, 79-90.
(30) Olah, G. A.; Parker, D. G.; Yoneda, N. J. Org. Chem. 1977, 42,
32-37.
(31) Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996, 61, 1702-
1706.

11220 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Crich and Sun
the chemical shifts of the anomeric protons in the triflates 31
and 32 (vide infra, δ 6.21 and 5.60, respectively). In both 16
and 25 the anomeric signal is a broad singlet, compatible with
either the R- or â-stereochemistry with a small unresolved 3J1,2
scalar coupling. Second, a gated decoupled 13C NMR spectrum
Scheme 3
1
of 16, recorded at -78 °C, revealed a JCH coupling of 184.5
Hz for the anomeric carbon which is fully consistent with an
R-mannoside carrying a somewhat electronegative substituent
at C1.34 NOE correlations between the anomeric proton and
H3 and/or H5, whose detection would definitely establish the
â-configuration, were not attempted due to the unresolved nature
of the majority of the ring protons and methoxy residues.
The differing stereoselectivity on coupling of 13 and 23 with
alcohols, as indeed that of their more preparatively useful
counterparts 1 and 8, respectively, is all the more intriguing in
view of the fact that both give a single triflate intermediate.
The formation of â-mannosides from the R-triflates 16 and 25
is entirely in accord with the SN2-like mechanism advanced in
Scheme 2, but that of R-mannosides from 25 demands an
alternative route. It is conceivable that the R-triflate (25) is in
equilibrium with a trace of its less stable but more reactive
â-anomer (33), much as in Lemieux’s bromide ion catalyzed
formation of R-glucosides from R-acetobromoglucose,35 but this
does not offer a satisfactory explanation for the difference
between the two series of compounds. Neither does such an
equilibrium provide an explanation for the inversion of stereo-
selectivity observed with the change in mixing order for 1
(Scheme 1).
problem in hand. However, we reasoned that a difference in
stability of 35 and 19 would be reflected in the more
experimentally accessible decomposition temperatures of the
precursor triflates 16 and 25 in the absence of effective
nucleophiles. Toward this end 16 and 25 were each prepared
in CD2Cl2, in the now standard manner by reaction of 13 and
23 with Tf2O and DTBMP at -78 °C, and allowed to warm
1
gradually with monitoring by H and 19F NMR spectroscopies
every 10 °C until the onset of decomposition, whereupon the
1
products were investigated by H NMR spectroscopy. In the
case of the 4,6-benzylidene-protected triflate 16 decomposition
began at -10 °C and provided, uniquely, the glycal 38 which
could be isolated in 95% yield. This species clearly arises from
rapid deprotonation of the oxacarbenium ion 19. In contrast,
decomposition of triflate 25 was evident at -30 °C and resulted
in the formation of a complex mixture of products from which
the R-methyl mannoside 26 and the thioglycoside 28 were
isolated in 61 and 5% yields, respectively. A number of minor
Plausible alternative mechanisms for R-glycoside formation
with 25 involve participation of the 6-O-Me group generating
a highly reactive R-donor 34 or simply invoke the oxacarbenium
ion 35. In the 4,6-benzylidene series a bridged species akin to
1
products were insufficently resolved, both by H NMR spe-
croscopy and on subsequent silica gel chromatography, and were
consequently not identified. We rationalize the formation of
26, and of the multiple, minor decomposition products, by
nucleophilic attack of one mannose residue upon the oxacar-
benium ion 35 of a second. One example of the many variations
possible is given in Scheme 3.
It is clear that the activation barrier for expulsion of the triflate
anion is higher in the 4,6-benzylidene series. Moreover, once
formed 19 decomposes rapidly by proton loss whereas 35
undergoes intermolecular nucleophilic attack by such poor
nucleophiles as ether oxygens. At a constant temperature of
-78 °C the equilibrium constant for formation of 19 from 16
will be much lower than that of 35 from 25 which satisfactorily
explains the difference in stereoselectivity of the two systems.
A further indication of the difference in stabilities of triflates
16 and 25 may be gleaned from the 13C NMR investigations.
At -78 °C in CD2Cl2 16 showed no decomposition over the
5-6 h required for aquisition, as judged from a 1H NMR
spectrum recorded immediately after the 13C, whereas 25 was
substantially decomposed in the same time frame so putting
the 13C data beyond reach.
34 is impossible but not the corresponding oxacarbenium ion
19. Without being able in any way to rule out participation by
the 6-O-Me group as in 34 in the conformationally labile system,
we were intrigued by the possibility that the difference in
selectivity between the two series was a factor of the relative
stabilities of 35 and 19, with the latter being significantly higher
in energy and so not making a significant contribution to the
reaction manifold. Support for this hypothesis may be gleaned
from the work of Fraser-Reid and co-workers wherein it was
demonstrated computationally that the slower hydrolysis of the
pentenyl glucoside 37 with respect to 36 was due to the torsional
strain engendered in the trans-fused 4,6-benzylidene group on
going to the sofa conformation of the intermediate oxacarbenium
ion.36 Direct experimental support for any difference in stability
of two such fleeting species as 35 and 19 is extremely difficult
to come by. Certainly, any direct measure by 1H or 13C NMR
spectroscopy in CD2Cl2 is not possible and any eventual
observation in superacid media of questionable relevance to the
Next, we turned our attention to the glucosyl donor 39 with
its potentially participating, stereodirecting 2-O-acetate group.
Reaction of this sulfoxide with Tf2O and DTBMP in CD2Cl2 at
-78 °C resulted in the formation of two new signals in the 19
F
NMR spectrum aside from unreacted Tf2O (δ 4.10). One of
these (δ -3.36) is assigned to DTBMPH+TfO- and the second
(δ 0.26) to an intermediate, triflate-bearing glycosyl donor. It
is noteworthy that benzenesulfenyl triflate (22) was again not
observed. The 1H NMR spectrum revealed consumption of the
substrate in favor of two new anomeric signals at δ 6.21, a
doublet with J ) 3.5 Hz, and 5.60, a double doublet with J )
7.6 and 2.3 Hz, in the ratio 1.4:1. Addition of methanol resulted
in the formation of the â-glycoside 40 and the ortho ester 41.
When the reaction was conducted on a slightly larger scale 40
(34) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-
297.
(35) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2214-
2221.
(36) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem.
1996, 61, 5280-5289.

Glycosyl Triflates in Sulfoxide Glycosylation
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11221
4JH1H3 W-type coupling of 2.3 Hz observed for the anomeric
proton. At the same time the 1S5 conformarion puts the â-triflate
group in a pseudoaxial position, so explaining the close
similarities in the 13C and 19F NMR spectra of the two triflates.
This conformation is a consequence of the strongly electrone-
gative nature of the triflate group and of the anomeric effect.
Although such conformations are somewhat unusual in the
glucopyranose series, Hall has previously discussed the tetraac-
etate of â-glucopyranosyl fluoride in terms of the closely related
3
1,4B conformation to explain the magnitude of the JH1H2
coupling constant. As here, the preference of the strongly
electronegative anomeric substituent for the (pseudo)axial
position was invoked to explain this conformation.37 Although
the triflates 31 and 32 are plainly identified as intermediates in
the chemistry of 39 and Tf2O, the isolation of two â-glucosides
(40) and (42) and the ortho ester 41 suggests that the actual
glucosylation reaction occurs at least in part through formation
of a transient acetoxonium ion 47 and that a similar mechanism
is operative for the perpivalated derivative (5) originally
employed by Kahne.1
Is it possible to detect other intermediates prior to the
formation of glycosyl triflates in this chemistry? In a recent
paper employing the sulfoxide 48 Boeckman and Liu noted the
formation of a very reactive intermediate on activation with Tf2O
at -90 °C, too unstable for use even at -78 °C, but which
rapidly glycosylated alcohols with high â-selectivity at -90
°C.10 Naturally, this comment aroused our curiosity and we,
therefore, repeated the reactions of 13, 23, and 39 with Tf2O in
CD2Cl2 at -90 °C in the hope of identifying 49 and its
congenors before collapse to the glycosyl triflates. In this we
were disappointed as the triflate was the only identifiable
carbohydrate product. It therefore seems likely that the unstable
intermediate identified by Boeckman was simply the R-triflate
whose PMB protecting groups rendered it unstable at higher
temperatures.
Finally, it is appropriate to ask, what is the ultimate fate of
the sulfenate moiety in these glycosylation reactions? As we
have seen, benzenesulfenyl triflate (22) is a powerful electrophile
and reacts with the sulfoxide more rapidly than Tf2O, presum-
ably resulting in the formation of the unknown sulfenic
anhydride 50. The chemistry of such unstable species is
complex, and we have made no attempt to characterize it. We
only point out here that in all of these reactions diphenyl
disulfide is one of the several byproducts observed which must
ultimately derive from 22 and/or 50. Likewise, we note the
isolation of the thioglycosides 17, 28, and 42 as byproducts in
some of our reactions. The implication is that thiophenol is
also produced in the decomposition of 22 and/or 50, which must
involve a series of disproportionation reactions.38
and 41 were isolated in 39% yield each, together with 19% of
the â-thioglycoside 42. It is clear from the 1H NMR spectrum
that two carbohydrate-derived intermediates are formed in this
reaction, yet in the 19F NMR spectrum, only one signal is
observed, aside from Tf2O and DTBMPH+TfO-, hinting that
the two species are very similar types of triflates. These might
be two anomeric triflates 31 and 32, or two diastereomeric ortho
esters 43 and 44. To distinguish between the two possibilities
a 13C NMR spectrum was recorded at -78 °C. Eight resonances
corresponding to carbonyl carbons were detected at δ 171.8,
171.9, 172.3, 172.4, 172.5, 172.9, 173.0, and 173.1, but only a
single anomeric carbon at δ 102.9 could be identified. No
evidence was found for ortho ester carbons. Thus, both the 1H
NMR spectrum and the number of carbonyl carbons in the 13
C
NMR spectrum indicated a mixture of two carbohydrates,
whereas our inability to identify two anomeric carbons or triflate
ester signals suggested that these must be very similar. The
1
gated decoupled 13C NMR revealed a JCH coupling constant
of 184.5 Hz, consistent with an R-anomer.34 However, the more
downfield of the two lines in the doublet assigned to C1 had a
w1/2 of ∼ 10 Hz, suggesting that the doublet was in fact two
very similar, superimposed doublets with closely related cou-
pling constants and chemical shifts. In subsequent variable-
temperature experiments, involving gradual warming of the
initial 1.4:1 mixture of 31:32, the anomeric ratio was seen to
be a function of temperature, increasing to 3.8:1 in favor of 31
before the onset of decomposition around 0 °C. The increased
ratio was mirrored by a corresponding simplification of the 13
C
NMR spectrum at the higher temperatures. Both substances
decomposed at around 0 °C with the minor one doing so more
rapidly, as judged by 1H NMR spectroscopy. No attempt was
made to characterize the products of these decompositions. Very
revealingly, if a -10 °C solution was recooled to -78 °C, the
original product ratio was essentially restored, indicating that
the two substances are in dynamic equilibrium. This last
observation is sufficient in itself to exclude the possibility that
either one of the two substances is the initial sulfonium salt
(45). The complete data set is best interpreted in terms of two
triflates (31) and (32). The R-anomer (31) predominates and
adopts the standard 4C1 conformation as indicated by the 3JH1H2
Conclusion
The answer to the title question is, at least for the three
examples studied, a resounding yes. Glycosyl triflates are
intermediates in the sulfoxide glycosylation method when the
sulfoxide is activated with Tf2O prior to addition of the glycosyl
acceptor. As suggested in Scheme 2, method A, the possible
exception involves activation of the sulfoxide in the presence
of the acceptor, which is more nucleophilic than triflate anion.
The stability of the anomeric triflates formed is a function of
the protecting groups and, doubtless, the solvent. Kahne’s
intermediate glycosyl donor, reactive to hindered alcohols at
low temperature yet stable in toluene for prolonged periods at
room temperature, was most likely the glycosyl triflate. The
1
coupling constant in the H NMR spectrum. The minor, less
1
stable â-anomer (32) must exist substantially in the S5 twist
3
boat conformation 46 which gives rise to the reduced JH1H2
coupling constant, smaller than that typically found in â-glu-
copyranosides in the C1 conformation, and which permits the
(37) Hall, L. D. Can. J. Chem. 1969, 47, 1-17.
(38) Freeman, F. Chem. ReV. 1984, 84, 117-135.
4

11222 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Crich and Sun
sulfoxide method is a very convenient means of generating
glycosyl triflates in situ in essentially quantitative yield. It is
not the purpose of this paper to delineate the precise mechanism
of glycoside formation subsequent to formation of the triflate.
Indeed, this will be substrate-dependent and very much a
function of a the protecting groups and solvent. In some
instances glycoylation will occur via the intermediacy of
transient ion pairs in an SN1-like manner. In others, when the
protecting groups are disarming either by virtue of their
electronegativity or for torsional reasons, the glycosylation
reaction will follow an SN2-like pathway. In yet others,
neighboring group participation through transient dioxolenium
ions, e.g. 47, can be expected to play a role. Such details, which
will need to be worked out for each individual case through
kinetic studies, are beyond the scope of this study. However,
it is very likely that in the 4,6-benzylidene-protected series
R-mannosyl triflates are displaced SN2-like in dichloromethane
at low temperatures to give â-glycosides. The reactivity of
glycosyl triflates and the high stereoselectivity achieved with
them and other anomeric sulfonate esters in glycosylation
reactions had been previously noted by Schuerch33,39-41 but little
exploited because of the difficulty involved in their generation
at the time. In light of these results it would seem entirely
reasonable that glycosyl triflates are immediates in a whole range
of glycosylation reactions employing AgOTf or TMSOTf as
activating species, at least when activation is carried out prior
to addition of the glycosyl acceptor. Indeed, Schuerch suggested
in 1973 that glycosyl triflates were intermediates in the AgOTf-
mediated coupling of pyranosyl bromides with alcohols.39 In
full agreement with the conditions noted here, Schuerch reported
that couplings could be conducted very efficiently at -78 °C
in dichloromethane in a matter of minutes.39 In subsequent
work, Hanessian also reported the coupling of glycosyl bromides
with alcohols mediated by AgOTf but conducted his reactions
for periods of several hours at 0 °C.42 Apparently, such
temperatures and reaction times were unnecessary as more recent
work from the same laboratory is described as proceeding
rapidly and efficiently at -78 °C, in agreement with Schuerch
and ourselves.43 Perlin and co-workers studied the coupling of
pyranoses and alcohols mediated by triflic anhydride and
considered that the aldose reacts with the anhydride to give a
glycosyl triflate.44,45 However, under the unspecified reaction
conditions employed, the products of the reaction of the
pyranose with triflic anhydride were found to be unstable and
to be unsuitable for glycosylation reactions. When the reaction
was conducted in the presence of Bu4NBr, the unstable
intermediate was converted to the pyranosyl bromide in high
yield, which could then be employed in glycosylation in the
usual manner.44,45 A later 19F NMR investigation of the reaction
of pyranoses with triflic anhydride or triflic acid at -40 °C in
dichloromethane, however, found no evidence for the formation
of glycosyl triflates as intermediates in this reaction and came
to the conclusion that the coupling reactions were simply
dehydrative reactions mediated by the strong acid H3O+TfO-
generated in situ.46,47
Experimental Section
General Procedures. NMR experiments were conducted at 300,
1
75, and 282 MHz for H, 13C, and 19F, respectively, using a Bruker
AC300 instrument equipped with a switchable QNP (1H, 13C, 19F, and
31P) probe enabling back-to-back data acquistion for the different nuclei
without the need to remove the sample or tune the probe. Chemical
shifts are downfield from tetramethylsilane for H and 13C NMR and
1
from trifluoroacetic acid for 19F NMR spectra. All solvents were dried
and distilled by standard techniques. Microanalyses were conducted
by Midwest Microlabs, Indianapolis, IN.
Phenyl 4,6-O-Benzylidene-2,3-di-O-methyl-1-deoxy-1-thio-r-D-
mannopyranoside (17). To a stirred mixture of the thioglycoside
phenyl 4,6-O-benzylidene-1-deoxy-1-thio-R-D-mannospyranoside48 (0.58
g, 1.6 mmol) and NaH (60%, 0.32 g, 8.0 mmol) in THF (10 mL) was
added MeI (0.60 mL, 9.7 mmol). Stirring was continued at room
temperature for 4 h before the reaction mixture was concentrated, and
the residue taken up with dichloromethane and washed with water,
saturated aqueous NH4Cl, and brine. Concentration and column
chromatography on silica gel (eluent: hexane/ethyl acetate ) 10:1)
afforded 17 (0.62 g, 100%): [R]D ) +166.7 (c ) 3.7, CHCl3); H
NMR (CDCl3), δ 3.53 (s, 3H), 3.60 (s, 3H), 3.74 (dd, J ) 3.1, 9.9 Hz,
1H), 3.88 (t, J ) 9.9 Hz, 1H), 3.93 (dd, J ) 1.4, 3.1 Hz, 1H), 4.17 (t,
J ) 9.9 Hz, 1H), 4.23 (dd, J ) 4.8, 9.9 Hz, 1H), 4.29-4.38 (m, 1H),
5.61 (s, 1H), 5.64 (d, J ) 1.4 Hz, 1H), 7.25-7.38 (m, 6H), 7.47-7.52
(m, 4H); 13C NMR (CDCl3), δ 58.9, 59.1, 64.9, 68.4, 77.7, 79.1, 80.3,
85.8, 101.6, 126.1, 127.6, 128.2, 128.9, 129.1, 131.3, 133.8, 137.4.
Anal. Calcd for C21H24O5S: C, 64.93; H, 6.23. Found: C, 64.60; H,
6.15.
20
1
Phenyl 4,6-O-Benzylidene-2,3-di-O-methyl-1-deoxy-1-thio-r-D-
mannopyranoside S-Oxide (13). To a stirred solution of 17 (0.93 g,
2.4 mmol) in dichloromethane (60 mL) at -78 °C was added MCPBA
(60%, 0.69 g, 2.4 mmol) followed by warming to -30 °C in 30 min.
The reaction was then quenched with saturated aqueous NaHCO3 and
washed with brine. Concentration and column chromatography on silica
gel (eluent: hexane/ethyl acetate ) 4:1) afforded 13 as a single,
20
unassigned isomer (0.83 g, 86%): [R]D ) +0.27 (c ) 2.6, CHCl3);
1H NMR (CDCl3), δ 3.43 (s, 3H), 3.63 (s, 3H), 3.72 (t, J ) 10.1 Hz,
1H), 4.00-4.09 (m, 2H), 4.15-4.22 (m, 2H), 4.27 (dd, J ) 1.3, 3.4
Hz, 1H), 4.53 (d, J ) 1.3 Hz, 1H), 5.59 (s, 1H), 7.34-7.38 (m, 3H),
7.47-7.51 (m, 2H), 7.56-7.60 (m, 3H), 7.65-7.69 (m, 2H); 13C NMR
(CDCl3), δ 59.1, 59.2, 68.0, 69.8, 74.9, 77.6, 78.0, 96.4, 101.7, 124.4,
126.0, 128.2, 129.0, 129.4, 131.8, 137.0, 141.5.
4,6-O-Benzylidene-2,3-di-O-methyl-r-D-mannopyranosyl Bro-
mide (18). To a stirred solution of the thioglycoside 17 (0.35 g, 0.90
mmol) in dichloromethane (12 mL) was added bromine (93 µL, 1.8
mmol) and the stirring continued for 20 min. Concentration and column
chromatography on silica gel (eluent: hexane/ethyl acetate ) 10:1)
20
afforded 18 as an unstable oil (0.23 g, 71%): [R]D ) +169.9 (c )
1
1.6, CHCl3); H NMR (CDCl3), δ 3.55 (s, 3H), 3.59 (s, 3H), 3.81-
3.90 (m, 2H), 4.00-4.17 (m, 3H), 4.28 (dd, J ) 4.6, 10.1 Hz, 1H),
5.59 (s, 1H), 6.50 (d, J ) 1.4 Hz, 1H), 7.35-7.40 (m, 3H), 7.47-7.51
(m, 2H); 13C NMR (CDCl3), δ 59.3, 59.6, 67.7, 67.8, 75.9, 78.4, 82.3,
86.5, 101.6, 126.0, 128.2, 129.0, 137.1.
Phenyl 2,3,4,6-Tetra-O-methyl-1-deoxy-1-thio-r-D-mannopyra-
noside (28). 28 was prepared from the R-phenylthio mannospyrano-
20
side49 similarly as for 17 in 98% yield: [R]D ) +136.9 (c ) 1.5,
1
CHCl3); H NMR (CDCl3), δ 3.38 (s, 3H), 3.46 (s, 3H), 3.48-3.69
(m, 10H), 3.84 (dd, J ) 1.6, 3.1 Hz, 1H), 4.06-4.13 (m, 1H), 5.66 (d,
J ) 1.6 Hz, 1H); 13C NMR (CDCl3), δ 57.7, 58.0, 59.1, 60.6, 71.2,
72.1, 76.2, 78.7, 81.5, 84.6, 127.2, 128.9, 131.0, 134.6. Anal. Calcd
for C16H24O5S: C, 58.51; H, 7.37. Found: C, 58.21; H, 7.51.
(39) Kronzer, F. J.; Schuerch, C. Carbohydr. Res. 1973, 27, 379-390.
(40) Srivastava, V. K.; Schuerch, C. Carbohydr. Res. 1980, 79, C13-
C16.
(41) Srivastava, V. K.; Schuerch, C. J. Org. Chem. 1981, 46, 1121-
1126.
(42) Hanessian, S.; Banoub, J. Carbohydr. Res. 1977, 53, C13-C16.
(43) Lou, B.; Huynh, H. B.; Hanessian, S. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Dekker: New York, 1997; pp 431-448.
(44) Leroux, J.; Perlin, A. S. Carbohydr. Res. 1978, 67, 163-178.
(45) Leroux, J.; Perlin, A. S. Carbohydr. Res. 1976, 47, C8-C10.
(46) Pavia, A. A.; Ung-Chhun, S. N. Can. J. Chem. 1981, 59, 482-
489.
(47) A very recent modification of this reaction has been described in
which the pyranose is activated with triflic anhydride in the presence of
diphenyl sulfoxide at -78 °C, prior to the addition of the acceptor alcohol.
Here, the order of mixing the reagents and the reactivity patterns described
suggest that a glycosyl triflate may be formed as an intermediate. Garcia,
B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119, 7597-7598.
(48) Tetsuta, O.; Masahiro, T.; Susuma, K. Tetrahedron Lett. 1994, 35,
6493-6496.
(49) Katsunori, K.; Toshio, K.; Hiroshi, M. Tetrahedron Lett. 1980, 21,
3771-3774.

Glycosyl Triflates in Sulfoxide Glycosylation
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11223
Phenyl 2,3,4,6-Tetra-O-methyl-1-deoxy-1-thio-r-D-mannopyra-
noside S-Oxide (23). Prepared similarly to 13, as a single, unassigned
Reaction of 23 with Tf2O and DTBMP at -78 °C: Isolation of
26, 27, and 28. To a solution of the sulfoxide 23 (9.3 mg, 0.027 mmol)
and DTBMP (11.3 mg, 0.054 mmol) in CD2Cl2 (1.4 mL) in a 5 mm
NMR tube at -78 °C was added Tf2O (5.7 µL, 0.035 mmol). The
glycosyl triflate 25 [1H NMR δ 6.17 (anomeric H); 19F NMR δ -0.033]
was instantly formed. Other signals were observed at δ 4.29 (Tf2O)
and -3.07 (DTBMPH+TfO-) in the 19F NMR spectrum. After the
addition of MeOH (4.4 µL, 0.11 mmol), the triflate 25 was consumed
immediately, giving the glycosides 26 and 27 (∼1:1). On a larger scale
(60.0 mg of 23), the isolated products were as follows: 27, 40%; 26,
26%; 28, 12%. 26 51 and 2751 are identified by their anomeric protons
at δ 4.80 (d, J ) 1.8 Hz) and 4.30 (br. s), respectively. 28 was identical
with the above authentic sample.
20
1
isomer, in 94% yield: [R]D ) -46.5 (c ) 1.9, CHCl3), H NMR
(CDCl3), δ 3.35 (2 x s, 6H), 3.47-3.62 (m, 9H), 3.82 (dd, J ) 3.3, 9.3
Hz, 1H), 3.89-3.95 (m, 1H), 4.19 (dd, J ) 1.7, 3.3 Hz, 1H), 4.54 (d,
J ) 1.7 Hz, 1H), 7.51-7.55 (m, 3H), 7.65-7.68 (m, 2H); 13C NMR
(CDCl3), δ 57.9, 58.2, 59.2, 60.7, 71.4, 73.5, 75.3, 77.3, 80.9, 94.9,
124.4, 129.1, 131.4, 141.8. Anal. Calcd for C16H24O6S: C, 55.80; H,
7.02. Found: C, 55.73; H, 7.05.
2,3,4,6-Tetra-O-methyl-r-D-mannopyranosyl Bromide (24). An
20
unstable oil prepared similarly to 18 in 74% yield: [R]D ) +196.8
(c ) 2.5, CHCl3); 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.46 (s, 3H), 3.49
(s, 3H), 3.50 (s, 3H), 3.51-3.65 (m, 3H), 3.71-3.79 (m, 2H), 3.89
(dd, J ) 3.3, 9.6 Hz, 1H), 6.53 (bs, 1H); 13C NMR (CDCl3) δ 57.9,
59.0, 59.1, 60.7, 70.4, 75.4, 75.5, 79.6, 80.7, 87.1.
Thermal Decomposition of Triflate 25. 25 was generated from
23 at -78 °C as in the above experiment and allowed to warm at 10
°C/10 min with monitoring by 1H and 19F NMR spectroscopies.
Decomposition began at -30 °C and led to a complex mixture from
which 26 and 28, identical with authentic samples, were isolated in 61
and 5% yields, respectively.
Reaction of 13 with Tf2O and DTBMP at -78 °C: Isolation of
14, 15, and 17. To a solution of the sulfoxide 13 (11.1 mg, 0.027
mmol) and DTBMP (11.3 mg, 0.055 mmol) in CD2Cl2 (1 mL) in a 5
mm NMR tube at -78 °C was added Tf2O (5.1 µL, 0.030 mmol). The
glycosyl triflate 16 [anomeric δH: 6.20; anomeric δC: 104.6 (1JCH 184.5
Hz); δF: -0.037] was instantly formed. Other signals in the 19F NMR
spectrum were located at δ 4.26 (Tf2O) and -3.21 (DTBMPH+TfO-).
Then, after the addition of MeOH (4.4 ul, 0.11 mmol), 1H and 19F NMR
spectroscopies indicated that the triflate 16 was consumed immediately
to give the mannosides 14 and 15 (1:7). In a larger scale reaction (61.0
mg of 13), the isolated products were as follows: 15, 53%; 14, 9%;
Generation of Mannosyl Triflate 25 from Bromide 24. To AgOTf
(51.4 mg, 0.20 mmol) in a 5 mm NMR tube at -78 °C was added a
cold solution of the glycosyl bromide 24 (12.0 mg, 0.040 mmol) and
DTBMP (32.9 mg, 0.16 mmol) in CD2Cl2 (1.5 mL) and the tube shaken
vigorously. 1H and 19F NMR spectra indicated the clean formation of
the glycosyl triflate 25 [1H NMR δ 6.17 (anomeric H); 19F NMR δ
-0.150]. On addition of MeOH (6.5 µL, 0.16 mmol) glycosides 26
and 27 were immediately formed (1:1).
20
1
17, 19%. 15: [R]D ) -53.1 (c ) 2.3, CHCl3); H NMR (CDCl3) δ
3.30-3.38 (m, 1H), 3.43 (dd, J ) 3.1, 9.9 Hz, 1H), 3.55 (s, 3H), 3.56
(s, 3H), 3.66 (s, 3H), 3.76 (dd, J ) 0.7, 3.1 Hz, 1H), 3.91 (t, J ) 10.3
Hz, 1H), 4.04 (t, J ) 9.9 Hz, 1H), 4.33 (dd, J ) 4.9, 10.3 Hz, 1H),
4.42 (d, J ) 0.7 Hz, 1H), 5.57 (s, 1H), 7.31-7.37 (m, 3H), 7.45-7.49
(m, 2H); 13C NMR (CDCl3) δ 57.4, 58.8, 62.0, 67.2, 68.5, 78.6, 78.7,
80.1, 101.5, 103.0, 126.0, 128.1, 128.8, 137.3. Anal. Calcd for
C16H22O6: C, 61.92; H, 7.15. Found: C, 61.71; H, 7.20. 14 50 is readily
identified by its anomeric signal at δ 4.79 (d, J ) 1.6 Hz). 17 was
identical with the above sample.
Reaction of 39 with Tf2O and DTBMP at -78 °C: Isolation of
40, 41, and 42. To a solution of the sulfoxide 39 (a mixture of
diastereomers at S)52 (9.5 mg, 0.021 mmol) and DTBMP (8.5 mg, 0.042
mmol) in CD2Cl2 (1.1 mL) in a 5 mm NMR tube at -78 °C was added
Tf2O (5.3 µL, 0.031 mmol). 1H and 19F NMR spectroscopies indicated
the instant formation of the glycosyl triflates 31 and 32 [1.4:1; 1H NMR
δ 6.21 (d, J ) 3.5 Hz, anomeric H, R-isomer) and 5.60 (dd, J ) 7.6
and 2.3 Hz, anomeric H, â-isomer); 19F NMR δ 0.25; 13C NMR δ 171.8,
171.9, 172.3, 172.4, 172.5, 172.9, 173.0, 173.1 (8 × carbonyl C), and
102.9 (1JCH 184.5 Hz, anomeric C)]. On addition of MeOH (3.4 µL,
0.083 mmol), both triflates were consumed immediately to give the
glycoside 40 and the ortho ester 41 (∼1:1). 4053 is identified by δ
4.43 (d, J ) 7.8 Hz) and 4154 by 5.73 (d, J ) 5.0 Hz) in the 1H NMR
spectrum. In a larger scale reaction (70.0 mg of 39), the isolated
products were 40 (39%), 41 (39%), and 4254 (19%).
Thermal Decomposition of Triflate 16. 1,5-Anhydro-4,6-O-
benzylidene-2,3-di-O-methyl-D-arabino-hex-1-enitol (38). 16 was
generated from 13 at -78 °C as in the above experiment and allowed
1
to warm at 10 °C per 10 min with monitoring by H and 19F NMR
spectroscopies. Decomposition began at -10 °C. 1H NMR spectros-
copy demonstrated that 38 was the exclusive product. Silica gel
chromatography enabled isolation of 38 in 95% yield: [R]D20 ) +1.8
(c ) 2.7, CHCl3); 1H NMR (CDCl3) δ 3.55 (s, 3H), 3.62 (s, 3H), 3.70-
3.86 (m, 2H), 3.99 (dd, J ) 7.3, 10.0 Hz, 1H), 4.24 (dd, J ) 0.9, 7.3
Hz, 1H), 4.36 (dd, J ) 4.4, 10.0 Hz, 1H), 5.59 (s, 1H), 6.18 (d, J )
0.9 Hz, 1H), 7.25-7.42 (m, 3H), 7.48-7.53 (m, 2H); 13C NMR (CDCl3)
δ 56.1, 59.2, 68.3, 68.8, 76.5, 79.7, 101.0, 126.0, 126.4, 128.2, 129.0,
137.0, 140.6. Anal. Calcd for C15H18O5: C, 64.74; H, 6.52. Found:
C, 64.59; H, 6.59.
Thermal Decomposition of Triflates 31 and 32. A mixture of 31
and 32 was generated from 39 at -78 °C as in the above experiment
1
and allowed to warm at 10 °C/10 min with monitoring by H and 19F
NMR spectroscopies. The initial ratio of 31:32 of ∼1.4:1 increased
to ∼3.8:1 before decomposition began around 0 °C, with the â-anomer
doing so more rapidly at that temperature. No attempt was made to
isolate or characterize products from this decomposition. At -10 °C
it was possible to attribute the following resonances in the 13C NMR
spectrum to the major isomer: δ 60.7, 66.8, 68.4, 68.5, 71.8, 103.4,
169.5 (2C), 169.9, 170.5.
Generation of Mannosyl Triflate 16 from Bromide 18. To AgOTf
(42.3 mg, 0.165 mmol) in a 5 mm NMR tube at -78 °C was added a
cold solution of the glycosyl bromide 18 (9.8 mg, 0.027 mmol) and
DTBMP (11.3 mg, 0.055 mmol) in CD2Cl2 (1.0 mL) with vigorous
shaking. 1H and 19F NMR spectroscopies indicated the essentially
quantitative formation of the glycosyl triflate 16 [1H NMR δ 6.20 (br.
s, anomeric H); 19F NMR δ -0.056] with only experimentally
insignificant chemical shift differences from the sample generated from
sulfoxide 13. On addition of MeOH (4.4 µL, 0.11 mmol), the
glycosides 14 and 15 (1:7) were immediately formed.
Reaction of 13 with PhSOTf and DTBMP at -78 °C. To AgOTf
(34.9 mg, 0.14 mmol) in a 5 mm NMR tube at -78 °C was added a
cold solution of PhSCl (7.9 mg, 0.054 mmol) in CD2Cl2 (0.5 mL), and
the tube was shaken vigorously at this temperature for 5 min. 19F NMR
spectroscopy indicated the formation of PhSOTf31 (19F NMR, δ -3.17).
Then a cold solution of the sulfoxide 13 (11.0 mg, 0.027 mmol) and
DTBMP (11.2 mg, 0.054 mmol) in CD2Cl2 (0.5 mL) was added at the
same temperature. 1H and 19F NMR spectroscopies indicated the
immediate formation of the glycosyl triflate 16 [19F NMR δ -0.122;
1H NMR δ 6.20 (anomeric H)]. On addition of MeOH (4.4 ul, 0.11
mmol), the mannosides 14 and 15 were formed (1:9).
Acknowledgment. We thank the NSF (CHE 9625256) for
support of this work.
Supporting Information Available: 1H and 19F NMR
spectra for the reactions of 13, 23, and 39 with Tf2O (6 pages).
See any current masthead page for ordering and Internet access
instructions.
JA971239R
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(54) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2199-
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