Direct synthesis of diastereomerically pure glycosyl sulfonium salts

Article abstract of DOI:10.1021/ol2009818

It is reported that stable glycosyl sulfonium salts can be generated via direct anomeric S-methylation of ethylthioglycosides. Mechanistically, this pathway represents the first step in the activation of thioglycosides for glycosidation; however, it can f

Full text of DOI:10.1021/ol2009818

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2928–2931
Direct Synthesis of Diastereomerically
Pure Glycosyl Sulfonium Salts
Laurel K. Mydock, Medha N. Kamat, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri;St. Louis,
One University Boulevard, St. Louis, Missouri 63121, United States
demchenkoa@umsl.edu
Received April 14, 2011
ABSTRACT
It is reported that stable glycosyl sulfonium salts can be generated via direct anomeric S-methylation of ethylthioglycosides. Mechanistically, this
pathway represents the first step in the activation of thioglycosides for glycosidation; however, it can further allow for the synthesis and isolation
of quasi-stable sulfonium ions, representing a new approach for studying these key intermediates.
Existing as the most abundant class of organic com-
pounds, carbohydrates are involved in a myriad of life-
sustaining and life-threatening processes.1 While Nature
flawlessly and repeatedly executes the glycosylation reaction
to yield complex poly- and oligosaccharides,2 chemical
installation of the glycosidic linkage remains cumbersome,
even with the aid of modern technologies.3ꢀ8 In the past
three decades, much effort has been dedicated to refining
glycosylation reaction conditions.9 However, enhance-
ments resulting from this effort are still not sufficient to
control the outcome of many glycosylations. Thioglyco-
sides serve as a prime example of this, even though they
have been one of the most studied and applied classes of
glycosyl donors.10 Among the various methodologies de-
veloped for thioglycoside activation, the alkylation path-
way is commonly accessed utilizing the methylating
reagent, MeOTf.11 It is assumed that the reaction begins
with the formation of a glycosyl sulfonium ion (Scheme 1),
which is quickly converted into other reaction intermedi-
ates, such as an oxacarbenium ion, glycosyl triflate (or a
combination thereof), and eventually a glycoside. While
the latter stages of glycosylation have been extensively
studied,12ꢀ14 the first activation step has never been pro-
ven, nor has the postulated sulfonium ion intermediate of
such glycosylation been isolated.
Since the pioneering studies by Schuerch et al.15 and Sun
et al.,16 there has been an increased interest in the detailed
investigation of anomeric sulfonium ions. Synthetic ap-
proaches to the formation of identifiable anomeric
sulfonium ions, however, are indirect and often lack stereo-
selectivity, or the products are contaminated with other
(1) Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.; Bertozzi,
C. R.; Stanley, P.; Hart, G. W.; Etzler, M. E. Essentials of Glycobiology,
2nd ed.; CSH Laboratory Press: New York, 2009.
(2) Hehre, E. J. Carbohydr. Res. 2001, 331, 347–368.
(3) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126,
14930–14934.
(4) Polat, T.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 12795–12800.
(5) Wang, C. C.; Lee, J. C.; Luo, S. Y.; Kulkarni, S. S.; Huang, Y. W.;
Lee, C. C.; Chang, K. L.; Hung, S. C. Nature 2007, 446, 896–899.
(6) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
(7) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007.
(8) Pornsuriyasak, P.; Ranade, S. C.; Li, A.; Parlato, M. C.; Sims,
C. R.; Shulga, O. V.; Stine, K. J.; Demchenko, A. V. Chem. Commun.
2009, 1834–1836.
(10) Zhong, W.; Boons, G.-J. In Handbook of Chemical Glycosylation;
Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, Germany, 2008; pp 261ꢀ303.
(11) Lonn, H. J. Carbohydr. Chem. 1987, 6, 301–306.
(12) Whitfield, D. M. Adv. Carbohydr. Chem. Biochem. 2009, 62, 83–159.
(13) Mydock, L. K.; Demchenko, A. V. Org. Biomol. Chem. 2010, 8,
497–510.
(14) Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153.
(15) West, A. C.; Schuerch, C. J. Am. Chem. Soc. 1973, 95, 1333–1335.
(16) Sun, L. H.; Li, P.; Zhao, K. Tetrahedron Lett. 1994, 35, 7147–7150.
(9) Demchenko, A. V. In Handbook of Chemical Glycosylation;
Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, Germany, 2008; pp 1ꢀ27.
r
10.1021/ol2009818
Published on Web 05/12/2011
2011 American Chemical Society

Scheme 1. Glycosidation of Thioglycosides
Scheme 3. Unexpectedly Low Yield of Disaccharide 5
Scheme 4. Formation and Hydrolysis of Salt 2a Monitored by
300 MHz 1H NMR in CDCl3
Scheme 2. Glycosyl Sulfonium Ions: (a) Obtained via Anomeric
Triflate;17,18 (b) Bicyclic Sulfonium Ions;19ꢀ21 (c) Obtained via
Direct Methylation of the Leaving Group (This Work)
species (Scheme 2a).17,18 The generation of bicyclic sulfo-
nium ions, wherein the anomeric sulfur is tethered else-
where to the sugar ring, has proven to be more
stereoselective (Scheme 2b), but their preparation requires
multiple synthetic steps.19ꢀ22 Furthermore, unlike other
classes of cyclic sulfonium salts (such as those used as
enzyme inhibitors),23 these anomeric reaction intermedi-
ates have been found to be relatively labile, existing mainly
in situ,24,25 and at low temperatures. Herein, we report a
simple and direct method to generate anomerically pure
sulfonium salts, such as 2a, that can be isolated, character-
ized, and stored (Scheme 2c).
between standard glycosyl acceptor 429,30 and glycosyl do-
nors 1 or 3 (in the presence of MeOTf) were both quenched
at 4 h. At this time, it was determined that the reaction
between 3 and 4 was complete. However, the progress of the
reaction between 1 and 4 was less clear, as there was a
significant amount of acceptor 4 remaining, but none of
glycosyl donor 1, and so it too was quenched for further
investigation. Upon analysis of the two reactions, it was
found that disaccharide 5 (derived from glycosyl donor
1), was only formed in 53% yield, whereas disaccharide
631 (from 3) was obtained in 84% yield (Scheme 3).
In further studying thioglycoside 1 in glycosylation, it
was noticed that concomitant with the formation of dis-
accharide 5, an unusually polar species also formed at the
baseline of the TLC plate (ethyl acetateꢀtoluene, 1/9, v/v;
forcomparison Rf (1) =0.55). InamorepolarTLC system
(methanolꢀCH2Cl2, 1/9, v/v), the unknown compound
was visualized as an elongated, yet well-defined, spot with
an Rf spanning 0.40ꢀ0.55. In addition, when subjected to
aqueous workup, it decomposed into the corresponding
hemiacetal 7(shown in Scheme 4). Based upon these findings,
it was hypothesized that this unknown “baseline species”
corresponded to anomeric glycosyl sulfonium salt 2a
(shown in Schemes 2 and 4), which was formed upon
methylation of the thioethyl leaving group. Upon repeat-
ing the reaction between 1 and 4, it was found that the
reaction required an additional 2 h (6 h total) for the
While expanding our investigations of the O-2/O-5 co-
operative effect26 to thioglycosides,27,28 we noted that
superdisarmed glycosyl donor 1 provided consistently
lower yields in glycosylation in comparison to that of
per-acylated glycosyl donor 3.11 Thus, the glycosylations
(17) Park, J.; Kawatkar, S.; Kim, J. H.; Boons, G. J. Org. Lett. 2007,
9, 1959–1962.
(18) Nokami, T.; Shibuya, A.; Manabe, S.; Ito, Y.; Yoshida, J.
Chem.;Eur. J. 2009, 15, 2252–2255.
(19) Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. J. Am. Chem. Soc.
2005, 127, 12090–12097.
(20) Beaver, M. G.; Billings, S. B.; Woerpel, K. A. J. Am. Chem. Soc.
2008, 130, 2082–2086.
(21) Stalford, S. A.; Kilner, C. A.; Leach, A. G.; Turnbull, W. B. Org.
Biomol. Chem. 2009, 7, 4842–4852.
(22) Fascione, M. A.; Adshead, S. J.; Stalford, S. A.; Kilner, C. A.;
Leach, A. G.; Turnbull, W. B. Chem. Commun. 2009, 5841–5843.
(23) Jayakanthan, K.; Mohan, S.; Pinto, B. M. J. Am. Chem. Soc.
2009, 131, 5621–5626.
(24) Boltje, T. J.; Kim, J.-H.; Park, J.; Boons, G.-J. Org. Lett. 2011,
13, 284–287.
(25) Concomitantly with this study Yoshida et al. discovered the
glycosyl sulfonium ion that can be stored at ꢀ80 °C for 24 h. Nokami, T.;
Nozaki, Y.; Saigusa, Y.; Shibuya, A.; Manabe, S.; Ito, Y.; Yoshida, J.
Org. Lett. 2011, 13, 1544–1547.
(26) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
(27) Premathilake, H. D.; Mydock, L. K.; Demchenko, A. V. J. Org.
Chem. 2010, 75, 1095–1100.
(28) Kamkhachorn, T.; Parameswar, A. R.; Demchenko, A. V. Org.
Lett. 2010, 12, 3078–3081.
(29) Kuester, J.M.;Dyong, I.Justus Liebigs Ann. Chem. 1975, 2179–2189.
(30) Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1–11.
(31) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269–4279.
Org. Lett., Vol. 13, No. 11, 2011
2929

baseline spot (2a) to completely disappear/react; markedly
improving the yield of disaccharide 5 to 87%.
In our attempt to isolate other sulfonium salts, per-
benzoylated (disarmed) thioglycoside 3 and its per-benzylated
(armed) counterpart, were each treated with MeOTf.
Other “superdisarmed” glycosyl donors equipped with
sulfur-based leaving groups (including S-phenyl, S-tolyl,
and S-benzoxazolyl) were also investigated for their
potential ability to form sulfonium ions. Although all glycosyl
donors underwent glycosidation in the presence of methyl
triflate, salt formation was only nominally observed in the
case of glycosyl donor 3, whereupon isolation attempts as
well as low temperature NMR monitoring were both
unsuccessful.31 These results made us believe that these
intermediatesulfonium salts are significantly morereactive
than ethylthioglycoside-derived salt 2a.
We next reacted thioglycoside 1 with MeOTf in the
absence of the glycosyl acceptor, which resulted in the near
exclusive formation of the anticipated sulfonium salt 2a
(in about 1 h). The reaction mixture was then concen-
trated and purified by preparative TLC (acetone/CH2Cl2,
1
3.5/6.5, v/v). H NMR and mass spectral analyses of the
isolated product were consistent with those expected for
ethylmethylsulfonium salt 2a. In comparing the 1H NMR
spectra of 1 vs 2a recorded at 300 MHz in CDCl3 (depicted
in Scheme 4), a downfield shift on a number of signals was
noted. Most significantly, was that of the anomeric H1
signal (Δδ = 0.59 ppm; while retaining β-configuration:
J
1,2 = 9.9 Hz) and the H7a,b signal, which corresponds to
Next, we decided to investigate the role that the (often
overlooked) counteranion could be playing. To accom-
plish this task, we chose to generate a variety of “methylat-
ing promoters” in situ. Methyl iodide, which alone is too
weak a promoter to activate S-ethyl glycosides, was chosen
as the source of a methyl cation (Meþ). On the other hand,
a series of commercially available silver salts (AgX, X =
BF4, PF6, ClO4, OTs, OMs, or NO3) were chosen as the
source of a counteranion, because these reagents alone also
do not promote thioglycoside glycosidations. As silver
compounds to readily undergo anion exchange with alkyl
halides (such asMeI), we were then able togenerate a series
of new “methylating promoters” in situ.34 Using these
reagents, a range of sulfonium salts (each containing a
different counteranion) could be generated in the absence
of the glycosyl acceptor as follows. Thioglycoside 1 was
stirred for 30 min with excess MeI (9 equiv), followed by
the addition of the desired silver salt (Table 1) to generate
the corresponding promoter. Accordingly, as the various
sulfonium salts began to form, the precipitation of yellow
AgI was noticed among the reactions between MeI and
AgBF4, AgPF6, and AgClO4, yielding sulfonium salts
2bꢀd (entries 1ꢀ3), which were purified by preparative
TLC. In the reactions between MeI and AgOTs, AgOMs,
or AgNO3, little-to-no AgI precipitate was observed, even
after 16 h implying that no sulfonium salt was formed.
Interestingly, unlike the solitary H-1 signal seen at 5.31 ppm
the methylene protons of the leaving group (Δδ = 0.75
ppm). The appearance of a new singlet at 2.44 ppm was
consistent with the newly acquired methylthio group.
Several other downfield shifts were also noticed, including
those of the H2, H3, and H5 protons. The mass spectrum of
2a exhibited an ion peak at m/z 641.2219 (calculated for
C37H37O8Sþ, 641.2209).
1
A follow-up H NMR spectrum recorded after 16 h
revealed that salt 2a had hydrolyzed completely, and the
resulting mixture consisted of R/β-hemiacetal 7 and liber-
ated ethylmethylsulfide (Scheme 4). On a side note, ex-
posure of salt 2a to methanol, gave rise to the exclusive
formation of an R-methyl glucoside. Thus, attempts to
record the spectrum in CD3OD, gave rise to a follow-up
spectrum (after 16 h) of 8a, and the use of methanol in
preparative TLC yielded 8b as the sole product (spectrum
shown in Scheme 4). It is noteworthy that the isolated 2a
yielded a similar glycosidation stereoselectivity to that
obtained in reactions wherein 2a was generated and allowed
to react with glycosyl acceptor in situ.
We attribute the unusual stability of 2a, to the electronic
consequences resulting from the “superdisarming” (2-O-
“nonparticipating alkyl”-3,4,6-tri-O-“electron-withdraw-
ing acyl”) protecting group motif.26,28 This protecting
group combination renders leaving group departure en-
ergetically unfavorable, as the resulting carbocation inter-
mediate is incapable of achieving adequate stabilization.32
Although this low-reactivity donor was initially developed
to improve stereocontrol in the glycosylation reaction, it
was subsequently found to be invaluable in the chemose-
lective introduction of a transꢀcis or cisꢀcis oligosaccharide
pattern, which was not directly accessible by the traditional
armedꢀdisarmed technique.33 At present, it is this super-
disarmed approach that has allowed us, for the first time, to
detect, trap, and even isolate the key intermediates formed
during the glycosidation of thioglycosides.
1
in the spectrum of 2a (Scheme 4), the H NMR spectra
of sulfonium salts 2bꢀd recorded at 300 MHz in CDCl3
revealed the presence of two new downfield H-1 signals. As
exemplified in the reaction between 1 and MeI/AgClO4,
the NMR spectrum of 2d showed the new H-1 signals to be
at 5.30 and 5.17 ppm (varies slightly for each counteranion),
each having a coupling constant consistent with that of a
β-glycoside (9.7 and 9.8 Hz, respectively). Additionally, these
H-1 shifts could each be linked (via integration) to a different
set of S-ethyl protons, and to a new singlet indicative of an
(32) Note: While per-acylated glycosyl donors (such as 3) also suffer
from an electron deficiency, the positive charge acquired upon leaving
group departure can be better stabilized through acyloxonium ion
formation. In fact, although a faint baseline spot could be also detected
during the glycosidation of 3, our attempts to isolate this species have
been unsuccessful.
(33) Fraser-Reid, B.; Udodong, U. E.; Wu, Z. F.; Ottosson, H.;
Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927–942
and references therein.
(34) Note: It should be noted that assuming the independent ex-
istence of such new MeX species is not entirely correct, as it is more likely
that the methylation of the leaving group would occur concomitantly
with counteranion exchange through a more complex transition state.
Herein, however, it is referred to as such for the purpose of simplifica-
tion. To verify that no reaction took place prior to the generation of the
active promoter in situ, two glycosylations were attempted in the
presence of MeI and separately in the presence of the silver salt (AgX),
wherein no reactions were observed.
2930
Org. Lett., Vol. 13, No. 11, 2011

Table 1. Formation of β-Sulfonium Salts 2bꢀd Using in Situ
Generated Methylating Promoters
entry
AgX
promoter34
time
salt
Figure 1. Structures of sulfonium salts 2da, 2db, 2e, and 2f.
1
2
3
AgBF4
AgPF6
AgClO4
MeBF4
MePF6
MeClO4
0.5 ha
0.5 ha
0.5 ha
2b
2c
2d
studying the means by which these intermediates convert
into glycoside products can contribute to understanding the
reaction mechanisms of glycosylation. For instance, while
Boons et al. found that the glycosidation of sulfonium salts
results in excellent SN2-like stereoselectivity,17,19,39,40 sev-
eral research groups have conversely encountered poor or
unanticipated anomeric selectivities when dealing with these
key intermediates. Yoshida et al. found that both the R- and
β-sulfonium species fail to undergo the anticipated
inversion.18 Likewise, Woerpel et al. found an intramole-
cular glycosyl sulfonium species which also failed to yield an
inverted product, giving, instead, a stereoselectivity arising
from the predominance of the open cation (SN1) pathway
over a concerted (SN2) displacement.20,41 Thus, due to such
experimental inconsistencies, we anticipate that the simple
approach to glycosyl sulfonium ions described herein will
aid in the investigation of traceable reaction intermediates
in glycosylation. This discovery may also offer a reliable
system for studying the controversial reaction mechanism
by which anomeric sulfonium ions are displaced by nucleo-
philes. It is our belief that a carefully controlled reaction
pathway will ultimately lead to the development of a highly
stereocontrolled glycosylation. This study may ultimately
impact areas outside of the glycosciences, as sulfonium salts
of similar structural composition have been found to be
valuable substrates42,43 and reagents44 in synthetic chemis-
try and represent valuable targets for computational
studies.45
a Time at which significant amount of AgI formation was detected.
acquired methyl group (see the Supporting Information
(SI)). Since rest of the signals remained overlapping we believe
that these were diastereomeric β-sulfonium salts (2da and
2db, Figure 1), as has been previously documented.17
As an extension of our findings with β-sulfonium salt 2a,
we also attempted to synthesize its R-epimer (2e, Figure 1).
Immediately, it became apparent that the reactivity of 2e is
much greater than that observed with its β-counterpart 2a,
and only small amounts of 2e were detected. Interestingly,
traceable 2e could only be generated when utilizing the
in situ generated promoters MeI/AgBF4 and MeI/AgPF6,
and no saltwas observed withMeOTf. Thecrude1H NMR
spectra of 2e revealed the presence of two new R-anomeric
signals at around 6.21 and 6.31 ppm (see the SI). However,
the spectrum indicatedthe presence of large amountsofthe
starting material and byproduct. Reinforcing these find-
ings are the similar results found by both Yoshida and
Boons, wherein β-sulfonium species were found to be more
stable than their R-counterparts.17,18
We also found that when 1 was treated with dimethyl-
(methylthio)sulfonium triflate (DMTST),35,36 it too gave
rise to the baseline spot on TLC, indicative of a polar
sulfonium species. When attempts were made to isolate this
proposed thiomethylated salt (2f, Figure 1), this species was
found to be less stable than its methylated analog 2a. The1H
NMR of purified compound 2f recorded at 300 MHz in
CDCl3 contained a significant amount of hemiacetal 7, but
when a crude NMR of 2f was acquired, a new H-1 peak
could easily be identified at 6.45 ppm (see the SI). Although
the spectrum remains unclear and will require further
investigation we believe that the pyranose ring in 2f
may have undergone a conformational change,37 as the
NMR data was more indicative of a half-chair confor-
mation.38 Offurther interest was that, upon treatment of 2f
with a large access of p-toluenethiol, the corresponding R-
tolyl thioglycoside was obtained stereoselectively.
Acknowledgment. This work was supported by awards
from the NIGMS (GM077170) and NSF (CHE-0547566).
Dr. Winter and Mr. Kramer (UM;St. Louis) are thanked
for HRMS determinations.
Supporting Information Available. Experimental pro-
1
cedures, extended experimental data, H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(39) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed. 2005,
44, 947–949.
(40) Kim, J. H.; Yang, H.; Khot, V.; Whitfield, D.; Boons, G. J. Eur.
J. Org. Chem. 2006, 5007–5028.
In conclusion, we believe that further investigation
of quasi-stable reaction intermediates and expansion to
(41) Billings, S. B.; Woerpel, K. A. J. Org. Chem. 2006, 71, 5171–5178.
(42) Kim, S.; Lee, B. S.; Park, J. H. Bull. Korean Chem. Soc. 1993, 14,
654–655.
(43) Xu, Y.; Fletcher, M.; Dolbier, W. R., Jr. J. Org. Chem. 2000, 65,
3460–3465.
(35) Ravenscroft, M.; Roberts, R. M. G.; Tillett, J. G. J. Chem. Soc.,
Perkin Trans. 2 1982, 1569–1972.
(36) Fugedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, c9–c12.
(37) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056–4062 and references therein.
(38) Pedersen, C. M.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc.
2007, 129, 9222–9235.
ꢀ
(44) Kaczmarczyk, G.; Jonczyk, A. Synlett 1997, 921–922.
(45) Buckley,N.;Oppenheimer,N.J.J. Org. Chem. 1996,61, 8048–8062.
Org. Lett., Vol. 13, No. 11, 2011
2931