Versatile synthesis and mechanism of activation of S-benzoxazolyl glycosides

Article abstract of DOI:10.1021/jo0711844

(Chemical Equation Presented) As a part of a program for developing new efficient procedures for stereoselective glycosylation, a range of S-benzoxazolyl (SBox) glycosides have been synthesized. The mechanistic aspects of the SBox moiety activation for gl

Full text of DOI:10.1021/jo0711844

Versatile Synthesis and Mechanism of Activation of S-Benzoxazolyl
Glycosides
Medha N. Kamat, Nigam P. Rath, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, One UniVersity BouleVard,
St. Louis, Missouri 63121
demchenkoa@umsl.edu
ReceiVed June 10, 2007
As a part of a program for developing new efficient procedures for stereoselective glycosylation, a range
of S-benzoxazolyl (SBox) glycosides have been synthesized. The mechanistic aspects of the SBox moiety
activation for glycosylation via a variety of conceptually different pathways in the presence of thiophilic,
electrophilic, or metal-based promoters have been investigated.
Introduction
Recent years have witnessed a broad spectrum of research
dealing with the improvement of different aspects of carbohy-
drate chemistry. Among these, development of novel techniques
for stereoselective glycosylation and convergent oligosaccharide
synthesis occupy a special niche. In an effort to address these
issues, a variety of structurally diverse glycosyl donors have
been developed.6,7 In spite of significant progress, no glycosyl
donor that could solve all major challenges of the glycoside
and oligosaccharide synthesis has yet emerged.
Our laboratory has been investigating a family of cyclic
glycosyl thioimidates as complimentary glycosyl donors for di-
and oligosaccharide synthesis. The roles and applications of this
class of compounds have been recently reviewed.8,9 Our
preliminary investigations have determined that 1-S-thiazolinyl
(STaz)10,11 and 1-S-benzoxazolyl (SBox)12,13 derivatives bear
The field of carbohydrate chemistry has experienced explosive
growth over the last two decades. This outbreak is mainly
attributed to recent findings revealing the involvement of
carbohydrates and their conjugates in a variety of biological
processes including fundamental enzymatic and hormonal
activities, interaction with invaders such as bacteria and viruses,
and connection with the development, growth, and metastasis
of tumors, among others.1-5 The appreciation of the profound
involvement of carbohydrates in a variety of processes in living
organisms resulted in a strong demand for further investigation
of these molecules. As a result of considerable difficulties
associated with the isolation of pure natural glycostructures, the
development of new and versatile methods for their chemical
synthesis remains as a notable challenge for synthetic organic
chemists.
(6) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(7) Davis, B. G. J. Chem. Soc., Perkin Trans. 2000, 1, 2137-2160.
(8) El Ashry, E. S. H.; Awad, L. F.; Atta, A. I. Tetrahedron 2006, 62,
2943-2998.
(9) Pornsuriyasak, P.; Kamat, M. N.; Demchenko, A. V. ACS Symp. Ser.
2007, 960, 165-189.
(10) Demchenko, A. V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N.
N. Angew. Chem., Int. Ed. 2004, 43, 3069-3072.
(11) Pornsuriyasak, P.; Demchenko, A. V. Chem.sEur. J. 2006, 12,
6630-6646.
(1) Varki, A. Glycobiology 1993, 3, 97-130.
(2) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(3) Essentials of Glycobiology; Varki, A., Cummings, R., Esko, J., Freeze,
H., Hart, G., Marth, J., Eds.; Cold Spring Harbor Laboratory Press: Cold
Spring Harbor, NY, 1999.
(4) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357-2364.
(5) Ritchie, G. E.; Moffatt, B. E.; Sim, R. B.; Morgan, B. P.; Dwek, R.
A.; Rudd, P. M. Chem. ReV. 2002, 102, 305-319.
10.1021/jo0711844 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/04/2007
6938
J. Org. Chem. 2007, 72, 6938-6946

Synthesis and Mechanism of ActiVation of S-Benzoxazolyl Glycosides
major positive traits of a modern glycosyl donor: accessibility,
odorless preparation, stability toward many reaction conditions
employed in carbohydrate chemistry, mild and selective activa-
tion for glycosylation, and excellent stereoselectivity. In addition,
we have demonstrated the applicability of this class of com-
pounds to convergent oligosaccharide synthesis via a variety
of conceptually novel strategies.14-17 Other useful application
of glycosyl thioimidates in phosphorylation has also been
developed.18,19 Herein we present the synthesis of the SBox
derivatives along with the first mechanistic investigation of their
glycosidation.
precursors for the synthesis of the SBox glycosides. To explore
these possibilities, we performed a number of additional
experiments. The application of anomeric acetates as the starting
material proved to be feasible, although it was significantly less
efficient in comparison to the synthesis of the SBox glycosides
from glycosyl bromides. Somewhat reduced yields, rarely
exceeding 70-80%, and poor anomeric stereoselectivity were
typically achieved in these reactions. For example, compound
2 was obtained from pentaacetate 13 in 79% yield as a mixture
of anomers (R/â ) 1/3.5, entry 7, Table 1). In contrast, the
synthesis of STaz glycosides from anomeric acetates was
entirely stereoselective and high yielding.11
1,2-Anhydro derivatives were also found to be suitable
precursors for the introduction of the anomeric SBox moiety.
For example, Lewis acid catalyzed transformation of the epoxide
1429 (ZnCl2) gave the corresponding 2-hydroxyl SBox derivative
15 in 87% yield (entry 8, Table 1). Finally, the SBox glycosides
could be efficiently obtained from the corresponding ethyl
thioglycosides via a two-step conversion protocol. Thus, the
treatment of thioglycosides 16 and 18 with bromine followed
by the anomeric substitution with KSBox afforded the SBox
glycosides 17 and 19 in 79% and 75% overall yields, respec-
tively (entries 9 and 10, Table 1).
Glycosidation of the SBox Derivatives: Optimization of
the Reaction Conditions. In principle, a stable anomeric leaving
group should not depart on its own, or as a result of a simple
solvolysis-assisted bond dissociation between C-1 and the
anomeric heteroatom (sulfur, halogen, or oxygen). In this case,
the leaving group ability is usually enhanced with the use of a
suitable promoter. A promoter (P)-assisted leaving group (LG)
departure (route A f B f C, Scheme 1) results in the formation
of a neutral species (PLG). The resulting oxocarbenium
intermediate C will then react with the glycosyl acceptor (R′OH)
forming either 1,2-trans- or 1,2-cis-linked product E or G,
respectively.
The structure of a thioimidoyl leaving group contains two
nucleophilic (or basic) centers: harder nitrogen and softer sulfur.
Although certain activation pathways have already been pos-
tulated for thioimidates,12 evidence as to whether the glycosy-
lations actually follow these pathways is limited. We anticipated
that for thioimidates in general, soft thiophilic promoters, such
as I+, would preferentially proceed via the sulfur atom, whereas
harder electrophiles, Me+ or proton (H+), would arguably target
the nitrogen. The latter activation pathway resembles the remote
activation concept introduced by Hanessian.23,30 Taking into
consideration that electron delocalization would decrease the
electron density around the sulfur atom (H, Scheme 1), it is
also possible that a generic thioimidate may be relatively
unreactive toward I+. It is thereby reasonable that thioimidates
would react somewhat slower in comparison with S-alkyl
glycosides under these reaction conditions. These considerations
are supported by the fact that STaz derivatives were found to
be completely stable in the presence of NIS/catalytic TfOH,10
a source of I+ commonly used in S-alkyl/aryl glycosides
activation.31 Conversely, the increased electron density on the
nitrogen (H), as a consequence of charge delocalization, will
favor the use of a harder electrophiles, Me+ or H+, as the
Results and Discussion
Synthesis of the 1-SBox Derivatives. It should be noted that
the synthesis of peracetylated SBox derivative 2 from aceto-
bromoglucose 1 has been reported prior to our studies.20,21 We
expanded this methodology by optimizing the reaction condi-
tions and applying the improved protocol to bromides of the
D-gluco (1, 3, and 9), D-galacto (5 and 11), and D-manno (7)
series. Commercial 2-mercaptobenzoxazole (HSBox), an odor-
less solid, or its potassium salt (KSBox), easily prepared from
HSBox by treatment with K2CO3, were chosen as the aglycon
source. As a result of the successful coupling reactions, a series
of the SBox derivatives 2, 4, 6, 8, 10, and 12 have been obtained
in high yields of 87-96% (entries 1-6, Table 1). With the
exception of the synthesis of the SBox mannoside 8 (R/â )
1/1), all anomeric substitutions proceeded stereoselectively
affording 1,2-trans-linked SBox glycosides. Differently from the
synthesis of the STaz derivatives, the synthesis of which from
glycosyl halides was often accompanied by the formation of
1,2-dehydro derivatives and/or N-glycosides,11 exclusively S-
linked products 2, 4, 6, 8, 10, and 12 have been obtained herein.
We reasoned that similarly to that of glycosyl donors of other
classes,includingpreviouslyinvestigatedglycosylthioimidates,22-28
various synthetic precursors, such as anomeric acetates, 1,2-
anhydrosugars, or S-ethyl glycosides, could serve as suitable
(12) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett. 2003,
5, 455-458.
(13) Demchenko, A. V.; Kamat, M. N.; De Meo, C. Synlett 2003, 1287-
1290.
(14) Pornsuriyasak, P.; Gangadharmath, U. B.; Rath, N. P.; Demchenko,
A. V. Org. Lett. 2004, 6, 4515-4518.
(15) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215-3218.
(16) Pornsuriyasak, P.; Demchenko, A. V. Tetrahedron: Asymmetry
2005, 16, 433-439.
(17) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem.,
Int. Ed. 2005, 7123-7126.
(18) Ferrieres, V.; Blanchard, S.; Fischer, D.; Plusquellec, D. Bioorg.
Med. Chem. Lett. 2002, 12, 3515-3518.
(19) Euzen, R.; Ferrieres, V.; Plusquellec, D. J. Org. Chem. 2005, 70,
847-855.
(20) Zinner, H.; Pfeifer, M. Ber. 1963, 96, 432-437.
(21) Zinner, H.; Peseke, K. Chem. Ber. 1965, 98, 3515-3519.
(22) Mukaiyama, T.; Nakatsuka, T.; Shoda, S. I. Chem. Lett. 1979, 487-
490.
(23) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80,
c17-c22.
(24) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Au-Yeung, B. W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C.
H. J. Am. Chem. Soc. 1981, 103, 3215-3217.
(25) Reddy, G. V.; Kulkarni, V. R.; Mereyala, H. B. Tetrahedron Lett.
1989, 30, 4283-4286.
(26) Tsuboyama, K.; Takeda, K.; Torii, K.; Ebihara, M.; Shimizu, J.;
Suzuki, A.; Sato, N.; Furuhata, K.; Ogura, H. Chem. Pharm. Bull. 1990,
38, 636-638.
(27) Chen, Q.; Kong, F. Carbohydr. Res. 1995, 272, 149-157.
(28) Ramakrishnan, A.; Pornsuriyasak, P.; Demchenko, A. V. J. Car-
bohydr. Chem. 2005, 24, 649-663.
(29) Lemieux, R. U.; Howard, J. In Methods in Carbohydrate Chemistry;
Whistler, R. L., Wolfrom, M. L., Eds.; Academic Press: New York, London,
1963; Vol. 2, pp 400-402.
(30) Hanessian, S.; Lou, B. Chem. ReV. 2000, 100, 4443-4463.
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205.
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Kamat et al.
TABLE 1. Synthesis of 1-SBox Derivatives
activators. In addition, thioimidates can also be activated with
metal salts that may proceed via the interim complexation of
sulfur or nitrogen or even bidentately (I, Scheme 1), depending
on the nature of metal, ligands, conditions, etc.
range of glycosyl acceptors 20, 22, 25, and 29. Extended
experimental data are available as a part of the Supporting
Information.
It should be noted that the glycosidation of per-acetylated
derivative 2 was rather impractical. Side reactions including
hydrolysis of the glycosyl donor and acetylation of the acceptor
lead to somewhat low efficiency and yields. For example the
synthesis of the disaccharide 21 from acceptor 20 was achieved
in a modest 40% yield (entry 1, Table 2). This result was
improved with a very reactive glycosyl acceptor 22 in the
presence of a relatively mild promoter, copper(II) triflate. Thus,
the disaccharide 23 was obtained in an acceptable yield of 63%
(entry 2). In contrast, glycosidation of the perbenzoylated
derivative 4 with glycosyl acceptors 22 or 25 proceeded
effortlessly and afforded the corresponding disaccharides 24 and
26 in good yields, especially in the presence of more powerful
Taking into consideration that the oxazole ring of the SBox
moiety is aromatic (J, Scheme 1), it is possible that its activation
for glycosylation will not follow the exact pathways that have
been anticipated for a generic thioimidate. We expected the
sulfur atom of the SBox moiety to be relatively reactive
(similarly to that of S-alkyl glycosides and conversely to that
of the STaz glycosides) since its involvement in the resonance
would be minimal. In an effort to ascertain the verity of this
expectation, we investigated all proposed pathways, i.e., activa-
tion with metal salts, protic and Lewis acids, as well as thiophilic
and electrophilic reagents. The search for the best promoter(s)
was performed with glycosyl donors 2, 4, 10, and 17 and a
6940 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis and Mechanism of ActiVation of S-Benzoxazolyl Glycosides
SCHEME 1
SCHEME 2
under (Lewis) acid promoted reaction conditions, it could be
readily glycosidated in the presence of a stronger promoter, such
as AgOTf. It has been also determined that a combination of
AgOTf and catalytic TfOH provides even more potent promoter
system than either component alone. Further glycosylation
experiments revealed versatility of the SBox glycosides for the
synthesis of 1,2-cis and 1,2-trans glycosides.37
Glycosidation of the SBox Derivatives: Mechanistic Stud-
ies. As such, a variety of conceptually different activation
pathways are suitable for efficient glycosidation of the SBox
derivatives; yet, the exact involvement of the SBox leaving
group in the activation process remains unknown. We reasoned,
however, that an understanding of the driving forces behind the
glycosidation of these derivatives would reveal the mechanism
by which this leaving group departs during the displacement.
To this end, we embarked on a thorough mechanistic investiga-
tion of the activation conditions described.
Activation with NIS/cat. TfOH. Coupling of the glycosyl
donor 4 with glycosyl acceptor 25 in the presence of NIS,
catalytic TfOH, and molecular sieves in 1,2-DCE was chosen
as a standard reaction for the investigation of the reaction
mechanism. Particular care was taken of isolating and character-
izing UV-active species that formed along with the disaccharide
26, with the anticipation that this UV active species was a
derivative of the departed aglycon (SBox). Upon isolation,
characterization, and comparison with the literature data,38,39
we found that the UV active species was 2,2′-dibenzoxazolyld-
isulfide (BoxSSBox) 31 (Scheme 2). Formation of the disulfide
31 during the SBox glycosidation experiments can serve as a
strong (though not explicit) indication that I+-mediated activa-
tion proceeds via the sulfur atom. Thus, I+-promoted SBox
departure presumably results in the formation of ISBox, two
molecules of which generate the disulfide 31 and molecular
iodine. It should be noted that regardless of the species isolated
herein, it is not possible to unambiguously prove the activation
pathway (also true for the H+-promoted activation studies
described below). Although, to the best of our knowledge, no
mechanistic studies have been published to date, a similar
activation pathway was postulated and is generally accepted for
the activation of S-alkyl/aryl glycosides.40
MeOTf as promoter (entries 3 and 4). Typically, reactions in
the presence of NIS/TfOH or Cu(OTf)2 required extended
reaction time and gave somewhat lower yields of the products.
Even after 24-48 h of reaction, substantial amount of the
reactants could be recovered from these glycosylations. How-
ever, Cu(OTf)2 could also be efficiently used for the activation
of perbenzylated SBox glycoside 17. This observation is in
accordance with the reactivity trend described by Lemieux,32
Fraser-Reid,33 and others,34-36 whereby benzylated glycosyl
donors are significantly more reactive than their acylated
counterparts.
Thus, in the presence of Cu(OTf)2, the glycosylation of
acceptors 25 with benzylated donor 17 gave the corresponding
disaccharide 27 in 99% yield (entry 5). In addition, either silver
and methyl triflate also provided excellent results for glycosi-
dation of perbenzylated SBox glycoside 17. For example, the
synthesis of disaccharide 28 from acceptor 22 in the presence
of MeOTf was accomplished in 98% yield (entry 6). It should
be noted that while modest stereoselectivity was obtained with
perbenzylated donor 17, its 2-benzyltriacylated counterpart 10
provided complete stereoselectivity in the reaction with the
glycosyl acceptor 29. The disaccharide 30 was obtained in a
respectable yield of 92% with the use of AgOTf as a promoter
(entry 7). Interestingly, Cu(OTf)2 was virtually ineffective in
the case of the glycosyl donor 10 as no glycosidation took
place.
Activation by Protonation. We determined that glycosyl
donor 4 can be glycosidated with glycosyl acceptor 25 in the
presence of 0.11 molar equiv of TfOH in 1,2-DCE. Similarly
to the previous experiment, it was anticipated that the UV-active
species that could be detected along with the disaccharide 26
by TLC analysis of the reaction mixture derived from the
Disappointingly, neither protic or Lewis acid promoted
glycosylations could provide efficiency and yields that would
be comparable to the best examples. We observed that the
glycosyl donor undergoes rapid anomerization into the corre-
sponding R-SBox derivative. While the latter was entirely stable
(32) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056-4062 and references therein.
(33) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem.
1990, 55, 6068-6070.
(37) Kamat, M. N.; De Meo, C.; Demchenko, A. V. J. Org. Chem. 2007,
72, 6947-6955.
(38) Arbuzova, S. N.; Brandsma, L.; Gusarova, N. K.; Van der Kerk, A.
S. H. T. M.; Van Hooijdonk, M. J. M.; Trofimov, B. A. Synthesis 2000,
65-66.
(34) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1998, 1, 51-65.
(35) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.;
Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734-753.
(36) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, New York,
2000; Vol. 1, pp 427-448.
(39) Goyal, R. N.; Verma, M. S. Ind. J. Chem., Sec. A 1996, 35A, 281-
287.
(40) Oscarson, S. In Carbohydrates in Chemistry and Biology; Ernst,
B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, New York, 2000;
Vol. 1, pp 93-116.
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Kamat et al.
TABLE 2. Optimization of Glycosidation of the SBox Derivativesa
a Extended table can be found in the Supporting Information. b Abbreviations: MS, molecular sieves; DCE, 1,2-dichloroethane; DCM, dichloromethane.
1
c Acetyl migration was the major side reaction observed. d No formation of the â-anomer has been detected by H NMR (R/â > 95/5).
departed aglycon. Our goal was to verify whether 2-benzox-
azolethione (32a, thioamide, thione, “NHBox”) or 2-mercap-
tobenzoxazole (32b, thioimide, thiol, HSBox) had been formed
(Scheme 3). The departed aglycon was isolated by column
chromatography followed by crystallization and its structure was
determined to be HNBox (32a). This conclusion was based on
the NMR data and the X-ray crystal structure of the isolated
UV active compound. Also, by comparing the NMR and X-ray
crystallography data of the commercial and the isolated samples
we noted that 32a isolated from the reaction mixture was
essentially the same compound as the commercial 2-mercap-
tobenzoxazole. Again, regardless of the species isolated herein,
it is not possible to unambiguously prove the activation pathway
due to the probability for the departed species to tautomerize
(HSBox h NHBox).
Activation by Alkylation (MeOTf). Since the migration of
the methyl group would be less likely than that of a proton,41
we anticipated the activation via methylation with MeOTf would
provide more reliable information on the structure of the
departed aglycon. To this end, studies were performed with
glycosyl donor 2 under simplified glycosylation conditions in
the presence of 2-propanol as a glycosyl acceptor and in the
absence of molecular sieves (Scheme 4). Upon completion, the
reaction mixture was evaporated under reduced pressure and
(41) Zinner, H.; Niendorf, K. Chem. Ber. 1956, 89, 1012-1016.
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Synthesis and Mechanism of ActiVation of S-Benzoxazolyl Glycosides
TABLE 3. Comparative UV Absorption of RSBox and RNBox Derivatives
SCHEME 3
SCHEME 4
the UV-active compound was separated from isopropyl glyco-
side 33 and the remaining reactants by column chromatography.
Characterization of the UV-active compound and comparison
with the literature data42-44 made us believe that the UV active
species was S-methylated compound 34. To ensure that the
product had not undergone tautomerization during the course
of the reaction, we also quenched the identical reaction mixture
at an estimated 50% conversion. The experimental data sug-
gested both products to be identical (34). To rule out the
possibility of isomerization, we also performed NMR experi-
ments using commercial 2-mercaptobenzoxazole (32a) and
MeOTf. Even though we observed formation of the other
tautomer in a very small quantity (<5%), the major product
was identical to the compound isolated in the previous experi-
ments (34). Interestingly, if the crude reaction mixture containing
34 was subjected to purification by crystallization, thiocarbonyl
derivative 35 was obtained instead and its structure was
confirmed by X-ray crystallography and NMR. Evidently, in
spite of the hydrolysis, the S-methyl linkage remains intact.
In this context, it would be beneficial if we could operate
with a reliable shortcut or an empirical rule that would allow
one to determine whether the isolated compound is N- or
S-methylated (or N- or S-linked in general). Based on the
literature data for peracetylated SBox and NBox glycosides (2
and 36),21 we found that UV spectroscopy could adequately
serve our needs for the rapid and reliable structure determination.
To this end, it should be possible to unambiguously distinguish
the isomers by simple and reproducible comparison of the
absorption bands. Thus, the thioimide (SH) derivative will have
two narrow bands (λ) at around 280 and 290 nm (CdN),
whereas the thioamide (NH) will have a single broad band at
∼300 nm (CdS). A series of comparative UV experiments with
both S- and N-linked derivatives are summarized in Table 3.
J. Org. Chem, Vol. 72, No. 18, 2007 6943

Kamat et al.
SCHEME 5
preparation, and activation under relatively mild reaction
conditions. The activation pathways for glycosidation of the
SBox moiety under a variety of reaction conditions were
investigated in greater detail. As a result of these fundamental
mechanistic studies, we acquired sufficient information to
conclude that either MeOTf or AgOTf-promoted activation of
the SBox glycosyl donors proceeds via the anomeric sulfur atom.
It should be emphasized that future studies of protic or Lewis
acid-catalyzed activations may open new exciting perspectives
for the glycosidation of compounds of this class.
Experimental Part
Synthesis of 2-Benzoxazolethione, Potassium Salt (“KSBox”).
Anhydrous K2CO3 (0.91 g, 6.6 mmol) was added to a stirred
solution of 2-mercaptobenzoxazole (1.0 g, 6.6 mmol) in dry acetone
(7 mL). The reaction mixture was refluxed for 3 h at 60 °C, acetone
was then evaporated off, and the residue was dried in vacuo. UV
data: λ 262, 296 nm.
Synthesis of the SBox Glycosides. Typical Procedures for the
Preparation of the SBox Glycosides from Glycosyl Bromides.
Method A. Preparation of the SBox Glycosyl Donors 2, 4, 6,
and 8. 18-Crown-6 (0.6 mmol) and KSBox (3.45 mmol, prepared
from HSBox and K2CO3) were added to a stirred solution of a
glycosyl bromide (3.0 mmol) in dry acetone (4 mL) under an
atmosphere of argon. The reaction mixture was stirred for 1 h at
rt. Upon completion, the mixture was diluted with CH2Cl2 (30 mL)
and washed with 1% aq NaOH (15 mL) and water (3 × 10 mL).
The organic phase was separated, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (ethyl acetate-hexane gradient elution) to afford
the SBox glycoside.
Method B. Preparation of the SBox Glycosyl Donors 10 and
12. A solution of bromide 946,47 or 1148,49 (2.0 mmol) in dry toluene
was added dropwise to a stirred mixture of 2-mercaptobenzoxazole
(2.4 mmol) and K2CO3 (2.4 mmol) in dry acetone at 40 °C. The
reaction mixture was kept for 2 h at 50 °C and then for 16 h at rt.
Upon completion, the mixture was diluted with toluene (30 mL)
and washed with 1% aq NaOH (15 mL) and water (3 × 15 mL),
and the organic phase was separated, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexane gradient
elution) to afford the SBox glycoside.
Preparation of Disaccharides. Method A: Typical MeOTf-
Promoted Glycosylation Procedure. A mixture of the glycosyl
donor (0.11 mmol), glycosyl acceptor (0.10 mmol), and freshly
activated molecular sieves (3 Å, 200 mg) in 1,2-DCE or DCM
(0.5 mL) was stirred for 2 h under argon. MeOTf (0.33 mmol)
was added, and the reaction mixture was stirred for 2-24 h at room
temperature; then Et3N (0.5 mL) was added, the mixture was diluted
with CH2Cl2 (30 mL), the solid was filtered off, and the residue
was washed with CH2Cl2 (2 × 5 mL). The combined filtrate was
washed with water (4 × 10 mL), and the organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (ethyl
acetate-hexane gradient elution) to yield the corresponding di- or
oligosaccharide.
Unambiguously, the S-methyl linkage was determined in the
compound 34.
Activation by Complexation with Metal Ion (AgOTf). As
mentioned earlier, we were also interested in investigating
activation pathways via metal salts. To this end, our initial
experiments with SBox glycosyl donor 2 and 2-propanol as
glycosyl acceptor in the presence of AgOTf as promoter gave
an insoluble white amorphous powder, possibly a metal insertion
polymer of the type -(SBox-AgOTf)n-. Since its characteriza-
tion appeared cumbersome, we bypassed this challenge by
employing Yamamoto’s AgOTf-BINAP (2/1) complex (38)45
as a promoter. As a result of the reaction between glycosyl donor
2 and 2-propanol in the presence of promoter 38 a relatively
unstable SBox-inclusion complex 39 was isolated by direct
crystallization from the reaction mixture. The attachment point
(sulfur), and the component molar ratio AgOTf-BINAP-SBox
(2/1/2) was determined by X-ray crystallography (Scheme 5).
In brief, as a result of the mechanistic experiments presented
herein, we conclude that either MeOTf or AgOTf-promoted
activation of the SBox moiety proceed via the anomeric sulfur
atom.
Conclusions
Based on the results presented, we conclude that the SBox
glycosides can be successfully prepared from a variety of
synthetic precursors and applied as glycosyl donors for stereo-
selective glycosylation. These derivatives fulfill major require-
ments for a versatile glycosyl donor: accessibility, odorless
Method B: Typical AgOTf-Promoted Glycosylation Proce-
dure. A mixture the glycosyl donor (0.11 mmol), glycosyl acceptor
(0.10 mmol), and freshly activated molecular sieves (3 Å, 200 mg)
in 1,2-DCE or DCM (0.5 mL) was stirred under argon for 1.5 h.
(42) Beilenson, B.; Hamer, F. M. J. Chem. Soc. 1939, 143-151.
(43) Llinares, J.; Galy, J.-P.; Faure, R.; Vincent et Jose´ Elguero, E.-J.
Can. J. Chem. 1979, 57, 937-945.
(46) Brennan, S.; Finan, P. A. J. Chem. Soc., C 1970, 1742-1744.
(47) Excoffier, G.; Gagnaire, D. Y.; Vignon, M. R. Carbohydr. Res. 1976,
46, 215-226.
(48) Lemieux, R. U.; Kondo, T. Carbohydr. Res. 1974, 35, C4-C6.
(49) Kochetkov, N. K.; Klimov, E. M.; Malysheva, N. N.; Demchenko,
A. V. Carbohydr. Res. 1991, 212, 77-91.
(44) Harizi, A.; Romdhane, A.; Mighri, Z. Tetrahedron Lett. 2000, 41,
5833-5835.
(45) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360-
5361.
6944 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis and Mechanism of ActiVation of S-Benzoxazolyl Glycosides
Freshly conditioned AgOTf (0.22 mmol) was added, the reaction
mixture was stirred for 1-2 h at rt, then diluted with CH2Cl2
(30 mL), the solid was filtered off, and the residue was washed
with CH2Cl2 (2 × 5 mL). The combined filtrate was washed with
20% aq NaHCO3 (15 mL) and water (3 × 10 mL), and the organic
phase was separated, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(ethyl acetate-hexane gradient elution) to afford a di- or an
oligosaccharide derivative. Glycosylations in the presence of AgOTf
(0.22 mmol)/TfOH (0.022 mmol) or AgOTf (0.22 mmol)/AgCO3
(0.22 mmol) were performed in a similar fashion. In the latter case,
molecular sieves 4 Å were employed.
Method C: Typical Cu(OTf)2-promoted Glycosylation Pro-
cedure. A mixture the glycosyl donor (0.13 mmol), glycosyl
acceptor (0.10 mmol), and freshly activated molecular sieves
(4 Å, 200 mg) in 1,2-DCE or DCM (0.5 mL) or toluene: dioxane
(1:3, v/v, 1 mL) was stirred under argon for 1 h followed by addition
of freshly conditioned Cu(OTf)2 (141 mg, 0.39 mmol). The reaction
mixture was stirred for 16-48 h at rt and then diluted with
CH2Cl2 (30 mL), the solid was filtered off, and the residue was
washed with CH2Cl2 (2 × 5 mL). The combined filtrate was washed
with water (3 × 15 mL), and the organic phase was separated,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acetate-
toluene gradient elution) to yield the corresponding di- or oligosac-
charide.
4 and 28 using method B in 91% or by method C in 70% yield.
Analytical data for 24 were essentially the same as reported
previously.11
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-â-D-glucopyranosyl)-
2,3,4-tri-O-benzyl-R-D-glucopyranoside (26) was obtained using
method A or B or E from 4 and 2553 in 95 or 94% yield,
respectively. Analytical data for 26 were essentially the same as
reported previously.54
Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-D-glu-
copyranosyl)-R-D-glucopyranoside (27) was obtained using method
C from 17 and 25 in toluene-dioxane (1/3, v/v, 1 mL) in 95%
yield (R/â ) 6/1) or in 1,2-DCE in 99% yield (R/â ) 1.9/1).
Analytical data for 27 were essentially the same as reported
previously.55
6-O-(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl)-1,2:3,4-di-O-
isopropylidene-R-D-galactopyranose (28) was obtained from 17
and 22 using method A in 98% yield (R/â ) 1/1), method B in
78% yield (R/â ) 1.1/1), and method C in 90% (R/â ) 1.3/1).
These glycosylations were performed in 1,2-DCE (0.5 mL).
Compound 28 was also obtained from 17 and 22 by method C
using toluene-dioxane (1 mL, 3/1, v/v) as solvent in 89% yield
(R/â ) 5.4/1). Analytical data for 28 were essentially the same as
reported previously.56
Methyl 6-O-(3,4,6-tri-O-acetyl-2-O-benzyl-D-glucopyranosyl)-
2,3,4-tri-O-benzoyl-R-D-glucopyranoside (30) was obtained using
method B from 10 and 2957 in 92% yield (R only). Analytical data
for 30: Rf ) 0.54 (ethyl acetate-hexane, 3/7, v/v); [R]22 84.9
Method D: Typical NIS/TfOH (or NIS/TMSOTf)-Promoted
D
(c ) 1.0, CHCl3); 1H NMR δ 1.92, 194, 2.00 (3 s, 9H, 3 × COCH3),
Glycosylation Procedure.
A mixture the glycosyl donor
3.47 (m, 1H, H-6b), 3.44 (s, 3H, OCH3), 3.48 (dd, 1H, J2′,3′
)
(0.11 mmol), glycosyl acceptor (0.10 mmol), and freshly activated
molecular sieves (4 Å, 200 mg) in 1,2-DCE (0.5 mL) was stirred
under argon for 1.5 h. NIS (0.22 mmol) followed by TfOH or
TMSOTf (0.022 mmol) was added, the reaction mixture was stirred
for 30 min at rt and then diluted with CH2Cl2 (30 mL), the solid
was filtered off, and the residue was washed with CH2Cl2 (2 ×
5 mL). The combined filtrate was washed with 20% aq Na2S2O3
(15 mL) and water (3 × 10 mL), and the organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (ethyl
acetate-hexane gradient elution) to afford a disaccharide derivative.
Method E: Typical TfOH-Promoted Glycosylation Proce-
dure. A mixture of the glycosyl donor (0.11 mmol), glycosyl
acceptor (0.10 mmol), and freshly activated molecular sieves
(4 Å, 200 mg) in 1,2-DCE (0.5 mL) was stirred under argon for
1.5 h. TfOH (0.11 mmol) was added, the reaction mixture was
stirred for 30 min at rt and then diluted with CH2Cl2 (30 mL), the
solid was filtered off, and the residue was washed with CH2Cl2 (2
× 5 mL). The combined filtrate was washed with 20% aq NaHCO3
(15 mL) and water (3 × 10 mL), and the organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (ethyl
acetate-hexane gradient elution) to afford a disaccharide derivative.
Methyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-acetyl-â-D-
glucopyranosyl)-â-D-galactopyranoside (21) was obtained using
method A or B from 2 and 2050 in 33 or 40% yield, respectively.
Analytical data for 21 were essentially the same as reported
previously.51
9.9 Hz, H-2′), 3.76 (dd, 1H, J6a,6b ) 10.6 Hz, H-6a), 3.95 (dd, 1H,
H-6b′), 4.09-4.16 (m, 2H, J5′,6a′ ) 4.3 Hz, J6a′,6b′ ) 14.2 Hz, H-5′,
6a′), 4.29 (m, 1H, H-5), 4.52 (dd, 2H, J2 ) 12.2 Hz, CH2Ph), 4.66
(d, 1H, J1′,2′ ) 3.4 Hz, H-1′), 4.88 (dd, 1H, J4′,5′ ) 9.4 Hz, H-4′),
5.13-5.19 (m, 2H, J1,2 ) 3.8 Hz, J2,3 ) 9.6 Hz, H-1, 2), 5.37 (dd,
1H, J4,5 ) 9.4 Hz, H-4), 5.40 (dd, 1H, J3′,4′ ) 9.2 Hz, H-3′), 6.09
(dd, 1H, J3,4 ) 9.6 Hz, H-3), 7.09-7.92 (m, 20H, aromatic) ppm;
13C-NMR δ 20.9, 21.0 (x 2), 29.9, 55.8, 62.2, 67.0, 67.6, 68.8,
68.9, 69.9, 70.6, 71.9, 72.4, 73.4, 96.8, 96.9, 128.0 (×3), 128.2,
128.5 (×2), 128.6 (×2), 128.7 (×3), 129.0, 129.3, 129.4, 129.9
(×2), 130.1 (×3), 130.2, 133.3, 133.6, 133.8, 138.0, 165.6, 166.0,
166.1, 170.1, 170.3, 170.9; HR-FAB MS [M + Na]+ calcd for
C47H48NaO17 907.2789, found 907.2798.
Mechanistic Investigations (performed in the absence of
molecular sieves): 2,2′-dibenzoxazolyldisulfide (31): A mixture
the glycosyl donor 4 (50 mg, 0.069 mmol) and glycosyl acceptor
31 (29 mg, 0.062 mmol) in 1,2-DCE (0.5 mL) was stirred under
argon for 15 min. NIS (31 mg, 0.138 mmol) and TfOH (∼2 µL,
0.014 mmol) were added, and the reaction mixture was stirred for
30 min at rt. The reaction mixture was subjected to column
chromatography on a silica gel column without any further treatment
to yield the disaccharide 26 (42 mg, 65% yield) and the UV-active
compound 31 (9.6 mg, 47% yield). Analytical data for 31: Rf )
1
0.60 (acetone-hexanes-toluene, 1/2/4, v/v/v); H NMR δ 7.34-
7.37 (m, 2H, aromatic), 7.53 (m, 1H, aromatic), 7.71 (m, 1H,
aromatic); 13C NMR δ 110.9, 120.1, 125.3, 125.7, 142.1, 152.8,
160.1; HR-FAB MS [M + H]+ calcd for C14H9N2O2S2 301.0105,
found 301.0103. Analytical data for 26 were essentially the same
as reported previously.55
6-O-(2,3,4,6-Tetra-O-acetyl-â-D-glucopyranosyl)-1,2:3,4-di-O-
isopropylidene-R-D-galactopyranose (23) was obtained using
method C from 2 and 22 in 63% yield. Analytical data for 23 were
essentially the same as reported previously.52
2-Mercaptobenzoxazole (Benzoxazolinethione, 32a). A mixture
the glycosyl donor 4 (50 mg, 0.069 mmol) and glycosyl acceptor
6-O-(2,3,4,6-Tetra-O-benzoyl-â-D-glucopyranosyl)-1,2:3,4-di-
O-isopropylidene-R-D-galactopyranose (24) was obtained from
(53) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
275-278.
(54) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem.
Commun. 1989, 685-687.
(50) Valashek, I. E.; Shakhova, M. K.; Minaev, V. A.; Samokhvalov,
G. I. Zh. Obshch. Khim. 1974, 44, 1161-1164.
(51) Knoben, H.; Schuluter, U.; Redlich, H. Carbohydr. Res. 2004, 339,
2821-2833.
(52) Ito, Y.; Ogawa, T.; Numata, M.; Sugimoto, M. Carbohydr. Res.
1990, 202, 165-175.
(55) Eby, R.; Schuerch, C. Carbohydr. Res. 1975, 39, 33-38.
(56) Grayson, E. J.; Ward, S. J.; Hall, A. L.; Rendle, P. M.; Gamblin,
D. P.; Batsanov, A. S.; Davis, B. G. J. Org. Chem. 2005, 70, 9740-9754.
(57) Byramova, N. E.; Ovchinnikov, M. V.; Backinowsky, L. V.;
Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8-C11.
J. Org. Chem, Vol. 72, No. 18, 2007 6945

Kamat et al.
25 (29 mg, 0.062 mmol) in 1,2-DCE (0.5 mL) was stirred under
argon for 15 min. TfOH (61 µL, 0.21 mmol) was added, and the
reaction was monitored by TLC. Upon 75-100% consumption of
4, the reaction mixture was concentrated under reduced pressure.
The residue was coevaporated with CH2Cl2 (2 × 5.0 mL) and then
purified by column chromatography on silica gel. The UV-active
compound 32a was obtained in 55% yield (5.6 mg). Analytical
data for 32a were the same as reported for the commercial
compound. X-ray crystallography data were essentially the same
as reported and have been included in Supporting Information.
Analytical data for 26, also obtained herein (33 mg, 82%), were
essentially the same as reported previously.
was dissolved in 1,2-DCE (0.5 mL) and stirred under argon for 15
min. MeOTf (69 µL, 0.59 mmol) was added, and the reaction was
monitored by TLC. Upon 100% consumption of 32a, the reaction
mixture was concentrated under reduced pressure. The residue was
coevaporated with CH2Cl2 (2 × 5 mL) and then subjected to
crystallization in chloroform. The formed crystals were separated
and dried in vacuo to afford 35 in 60% yield (40 mg). Analytical
1
data for 35: Rf ) 0.5 (ethyl acetate-toluene, 1/9, v/v); H NMR
δ 2.69 (s, 3H, SCH3), 7.00 (broad s, 3H, NH3) 7.41-7.85 (m, 4H,
aromatic). X-ray crystallography data are given in the Supporting
Information.
SBox-AgOTf-BINAP Inclusion Complex (39). The AgOTf-
BINAP complex 38 (53 mg, 0.2 mmol), prepared in THF according
to the reported procedure,45 was added to the solution of donor 2
(50 mg, 0.1 mmol) and 2-propanol (7.2 µL, 0.09 mmol) in 1,2-
DCE (0.5 mL). The reaction mixture was stirred for 1.5 h at rt. A
mixture of ethyl acetate, ether, and hexanes (2 mL, 0.5/1.0/1.0 v/v/
v) was added to initiate crystallization. The crystals were separated
and dried in vacuo to afford complex 39 (6 mg, 5%). X-ray crystal
structure data for complex 39 are given in the Supporting Informa-
tion. Glycoside 33 was obtained in 65% yield (24 mg) by subjecting
the mother liquor to column chromatography on silica gel.
2-Methyl-2-mercaptobenzoxazole (34). A mixture of the gly-
cosyl donor 2 (50 mg, 0.1 mmol) and 2-propanol (7.2 µL,
0.09 mmol) in 1,2-DCE (0.5 mL) was stirred under argon for 15
min. MeOTf (36 µL, 0.3 mmol) was added, and the reaction
progress was monitored by TLC. Upon 75-100% consumption of
2, the reaction mixture was concentrated under reduced pressure.
The residue was coevaporated with CH2Cl2 (2 × 5.0 mL) and then
purified by column chromatography on silica gel to afford 34
(7.3 mg, 43%) and isopropyl 2,3,4,6-tetra-O-acetyl-â-D-glucopy-
ranoside 33 (24.7 mg, 68%). Analytical data for 34: Rf ) 0.5 (ethyl
1
acetate-toluene, 1/9, v/v); H NMR δ 2.78 (s, 3H, SCH3), 7.27
(m, 2H), 7.45 (dd, 1H), 7.62 (dd, 1H); 13C NMR δ 14.7, 110.6,
118.5, 124.0, 124.5, 142.2, 152.2, 165.9; EI-GC/MS m/z 122 (79),
132 (92), 150 (21), 165 (100) amu. Analytical data for 33 were
essentially the same as reported previously.58
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM077170) and the University of
MissourisSt. Louis Graduate School Dissertation Fellowship
(to M.N.K.) for financial support of this research; the NSF for
grants to purchase the NMR spectrometer (CHE-9974801) and
the mass spectrometer (CHE-9708640) used in this work; Dr.
R. S. Luo for assistance with 500 MHz 2D NMR experiments;
and Dr. R. E. K. Winter and Mr. J. Kramer for HRMS
determinations.
Compound 34 (31 mg, 95% yield) was also prepared by reaction
of 2-mercaptobenzoxazole 32a (30 mg, 0.19 mmol) with MeOTf
(69 µL, 0.59 mmol) in 1,2-DCE. For the related NMR experiment,
compound 32a (10 mg, 0.067 mmol) was dissolved in CDCl3
(0.7 mL) under argon. The resulting mixture was transferred to the
NMR tube, MeOTf (23 µL, 0.198 mmol) was added, and the tube
was sealed and then vigorously shaken. The formation of 34 was
Supporting Information Available: Extended Table 2, experi-
mental and characterization data for SBox glycosides, spectra for
all new compounds, and X-ray data for compounds 4, 10, 32a, 35,
and 39. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
monitored by H NMR.
2-(Methylthiocarbonyloxy)benzenaminium Trifluoromethane-
sulfonate (35). 2-Mercaptobenzoxazole 32a (30 mg, 0.19 mmol)
(58) Jansson, K.; Noori, G.; Magnusson, G. J. Org. Chem. 1990, 55,
3181-3185.
JO0711844
6946 J. Org. Chem., Vol. 72, No. 18, 2007