New glycomimetics: Anomeric sulfonates, sulfenamides, and sulfonamides

Article abstract of DOI:10.1021/jo0520386

The synthesis of a variety of new 1-thio-D-glucopyranose derivatives oxidized at the sulfur atom is described, including seven 1-C-sulfonic acids, three sulfonate esters, three sulfinate esters, an S,S′-diglycosyl thiolsulfonate and thiolsulfmate, four S-

Full text of DOI:10.1021/jo0520386

New Glycomimetics: Anomeric Sulfonates, Sulfenamides, and
Sulfonamides
Spencer Knapp,* Etzer Darout, and Benjamin Amorelli
Department of Chemistry & Chemical Biology, Rutgers - The State UniVersity of New Jersey, 610 Taylor
Road, Piscataway, New Jersey 08854
knapp@rutchem.rutgers.edu
ReceiVed September 28, 2005
The synthesis of a variety of new 1-thio-D-glucopyranose derivatives oxidized at the sulfur atom is
described, including seven 1-C-sulfonic acids, three sulfonate esters, three sulfinate esters, an S,S′-diglycosyl
thiolsulfonate and thiolsulfinate, four S-glycosyl sulfenamides, an S-glycosyl sulfinamide, and two
S-glycosyl sulfonamides. These compounds possess unusual anomeric functionality that might be resistant
or even inhibitory to normal enzymatic carbohydrate processing, and therefore, they may be of future
use in studies of enzyme inhibition, structure, mechanism, and function.
Introduction
by oxidation of respective thiazolines 1 and 2 with m-
chloroperoxybenzoic acid (m-CPBA) in the presence of ethanol
(Scheme 1). Further transformation of 5 to sulfonates 8 and 9
was also carried out. In this paper, we report the details of those
transformations, a generalization of the glycosyl 1-C-sulfonate
preparation, our unsuccessful attempts to transform the sul-
fonates into S-glycosyl sulfonamides, and finally a route to the
sulfonamide through the corresponding S-glycosyl sulfenamide
and sulfinamide.
Enzymes that recognize carbohydrates can be fooled by
biomimetics that bind but are not processed to product in the
usual way. Because understanding and manipulating the “nor-
mal” action of enzymes and other proteins is crucial to virtually
all aspects of biology and medicine, the need continually arises
to develop new structures with the potential to interact “abnor-
mally” with them. As an example, thioglycosides,1 in which a
sulfur atom replaces an oxygen atom at the anomeric carbon of
a normal substrate, have structures and properties similar to those
of O-glycosides, yet resist enzymatic action. Consequently, these
unnatural compounds can serve a variety of purposes in
bioorganic and medicinal chemistry investigations. Chart 1 lists
some representative thioglycoside mimetics, in particular those
for which assay results are available.2 A much larger list of
examples might also be identified from among C-glycosides,3
oximes,4 triazoles,5 disulfides,6 cross-metathesis products,7 and
many other mimetics. One factor that distinguishes thioglyco-
sides from most other neoglycoconjugates, however, is the
capacity of the divalent (sulfenyl) sulfur atom to be converted
to more highly oxidized forms (sulfinyl and sulfonyl), potentially
extending the range of interactions with proteins.
(2) Respective citations for Chart 1: (a) Knapp, S.; Vocadlo, D.; Gao,
Z.; Kirk, B.; Lou, J.; Withers, S. G. J. Am. Chem. Soc. 1996, 118, 6804-
6805. (b) MacDougall, J. M.; Zhang, X.-D.; Polgar, W. E.; Khroyan, T.
V.; Toll, L.; Cashman, J. R. J. Med. Chem. 2004, 47, 5809-5815. (c)
Bousquet, E.; Spadaro, A.; Pappalardo, M. S.; Bernardini, R.; Romeo, R.;
Panza, L.; Ronsisvalle, G. J. Carbohydr. Chem. 2000, 19, 527-541. (d)
Ciccotosto, S.; Kiefel, M. J.; Abo, S.; Stewart, W.; Quelch, K.; von Itzstein,
M. Glycoconjugate J. 1998, 15, 663-669. (e) Mizuma, T.; Hagi, K.; Awazu,
S. J. Pharm. Pharmacol. 2000, 52, 303-310. (f) Kiefel, M. J.; Beisner, B.;
Bennett, S.; Holmes, I. D.; von Itzstein, M. J. Med. Chem. 1996, 39, 1314-
1320. (g) Schnabelrauch, M.; Vasella, A.; Withers, S. G. HelV. Chim. Acta
1994, 77, 778-799. (h) Michael, K.; Wittmann, V.; Konig, W.; Sandow,
J.; Kessler, H. Int. J. Peptide Protein Res. 1996, 48, 59-70.
(3) Recent leading reference: Postema, M. H. D.; Piper, J. L.; Betts, R.
L. Synlett 2005, 1345-1358.
(4) Recent leading reference: Renaudet, O.; Dumy, P. Bioorg. Med.
Chem. Lett. 2005, 15, 3619-3622.
We recently reported8 the inadvertent synthesis of the glycosyl
1-C-sulfonate esters 5 and 6 and 1-C-sulfinate esters 3 and 4
(5) Recent leading reference: Pe´rion, R.; Ferrie`res, V.; Garc´ıa-Moreno,
M. I.; Ortiz Mellet, C.; Duval, R.; Garc´ıa Ferna´ndez, J. M.; Plusquellec, D.
Tetrahedron 2005, 61, 9118-9128.
(6) Recent leading reference: Gamblin, D. P.; Garnier, P.; Ward, S. J.;
Oldham, N. J.; Fairbanks, A. J.; Davis, B. G. Org. Biomol. Chem. 2003, 1,
3642-3644.
(1) (a) Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995-2999.
(b) Driguez, H. ChemBioChem 2001, 2, 311-318. (c) Driguez, H. Top.
Curr. Chem. 1997, 187, 85-116. (d) Horton, D.; Wander, J. D. In The
Carbohydrates. Chemistry and Biochemistry; Pigman, W., Horton, D., Eds.;
Academic Press: New York, 1980; Vol. IB, pp 799-842.
(7) Recent leading reference: Wan, Q.; Cho, Y. S.; Lambert, T. H.;
Danishefsky, S. J. J. Carbohydr. Chem. 2005, 24, 425-440.
(8) Knapp, S.; Darout, E. Tetrahedron Lett. 2002, 43, 6075-6078.
10.1021/jo0520386 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/13/2006
1380
J. Org. Chem. 2006, 71, 1380-1389

New Glycomimetics
CHART 1. Some Enzyme-Resistant Thioglycosides with
Interesting Activities
SCHEME 1
purified as the free sulfonic acid by Sephadex chromatography.
When the oxidation of 1 with m-CPBA was carried out entirely
at room temperature, a considerable amount of low Rf material
was apparent by TLC analysis. Chromatography on silica with
9:1 dichloromethane/methanol as the eluant gave the amino
sulfonate zwitterion 9 in 43% yield, in addition to 23% of 5.
The structure of 9 was secured by its N-acetylation to give 7,
which matched the material prepared previously.
A mechanistic framework to account for these observations
is proposed in Scheme 2. The first oxidation evidently takes
place at the sulfur atom9 of 1 and 2 (in contrast, the corre-
sponding GlcNAc oxazoline reacts on nitrogen10) to give an
S-oxide 10. This intermediate may open to the nitrilium ion
11, closure of which would lead to the thioxazine 12. Acid-
promoted ethanolysis of 12 would give an O-ethylsulfenate 15,
which could be oxidized further by m-CPBA11,12 to the
corresponding sulfinate 16 and sulfonate 17. Alternatively,
oxidation of thioxazine 12 at sulfur could give activated sulfinate
or sulfonate intermediates (13 or 14), and then ethanolysis at
sulfur would provide 16 and 17, respectively. What can be
ascertained about the order of the oxidation and ethanolysis
steps? Oxidation of sulfinate to sulfonate (3 to 5) under these
conditions (-15 °C) is indeed slow, as reported previously, but
does occur to some extent in the presence of ethanol, according
to a control experiment. An oxidation carried out with only 2
equiv of m-CPBA in dichloromethane/ethanol (quenched with
Results and Discussion
R-GlcNAc 1-C-Sulfonates. Treatment of the GlcNAc-thia-
zoline 1 with 4 equiv of buffer-washed m-CPBA at -15 °C
(bath temperature) in the presence of several equiv of ethanol
gave rise to a mixture of 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-
â-D-glucopyranosyl-1-C-sulfonic acid ethyl ester 5 and the
corresponding sulfinate ester 3 (one diastereomer only). The
structures of 5 and 3 (except for the configuration at sulfur)
were established by their mass and NMR spectra, which
resemble those of other 2-acetamido-2-deoxy-1-thio-R-D-glu-
copyranosides, and by the independent m-CPBA oxidation of
3 to 5. Oxidation of the analogous tri-O-benzyl GlcNAc-
thiazoline 2, which was prepared from 1 by deacetylation
followed by O-benzylation, likewise gave the corresponding
O-benzyl-protected esters 4 and 6.
(9) Bonini, B. F.; Maccagnani, G.; Mazzanti, G.; Zwanenburg, Z. Gazz.
Chim. Ital. 1977, 107, 289-292.
The sulfonic acid triethylammonium salt 7 was prepared from
5 by DBU-promoted elimination of ethylene, followed by
chromatography with triethylamine in the eluant (Scheme 1).
Deacetylation with catalytic methoxide gave 8, which was
(10) Clark, M. A.; Wang, Q.; Ganem, B. Tetrahedron Lett. 2002, 43,
347-349.
(11) Netscher, T.; Prinzbach, H. Synthesis 1987, 683-688.
(12) Braverman, S.; Duar, Y. Tetrahedron 1990, 46, 2975-2990.
J. Org. Chem, Vol. 71, No. 4, 2006 1381

Knapp et al.
SCHEME 2
SCHEME 3
bisulfite at -15 °C after 30 min) gave a product mixture that
consisted primarily of starting thiazoline 1 and the same sulfinate
ester 3 (one diastereomer only), but no more than a trace of 5,
and no other prominent carbohydrate products according to
NMR analysis in the anomeric C-H region. A separate
oxidation of 1 conducted with 4 equiv of m-CBPA and taken
through a temperature gradient of -10 °C (2 h) and then 23 °C
(1 h) produced sulfonate 5 only (84% yield from 1, Scheme 1).
These experiments suggest that 3 is the source of 5, although
the conversion is incomplete at the lower temperature. But what
is the source of 3, and why is it formed as a single diastereomer?
Oxidation of bicyclic thioxazine 12 from the (less hindered)
convex face ought to give 13 with predominantly the S
configuration at sulfur. Ethanolysis of 13 with inversion of
configuration at sulfur would then give the R (at sulfur)
diastereomer of 16. However, R-1-thioglucopyranosides are
known to oxidize to sulfoxides with high stereoselectivity at
sulfur attributable to conformational control by the exo-anomeric
effect (the less hindered sulfur lone pair oxidizes),13,14 and
comparable oxidation of the sulfenate ester 15 is thus predicted
to lead selectively to the R diastereomer of 16 directly.
Therefore, either route from 12 (oxidation then ethanolysis, or
ethanolysis then oxidation) could give 16 of the R configuration
at sulfur, but neither 13 nor 15, if formed, accumulates as an
intermediate, and 14 is not formed. One possible route to
sulfonate 5 can be ruled out: kinetically selective oxidation of
the S diastereomer of 3 (in the presence of the R diastereomer,
which would be left behind) cannot be operating because only
the R diastereomer of 3 is formed initially.
to give an imino ether derivative 18. Further m-CPBA oxidation
of the sulfenic acid,15 analogous to previous observations,16
would lead to 19 and then to 20. Hydrolysis of imino ethers
under acidic conditions to give D-glucosamine products similar
to 9 has also been reported.17 Alternatively, 20 could form at
the higher temperature by ring opening of 13 to a nitrilium ion
in the presence of ethanol, followed by oxidation of the sulfinic
acid 19 to sulfonate 20.
Thiazoline 1 is known to hydrolyze to the R-GlcNAc
mercaptan 21 in acidic methanol solution (Scheme 3).18 To
check whether some 21 might form by hydrolysis during the
reaction of 1 with m-CPBA, and thereby serve as an intermedi-
ate, the m-CPBA/ethanol reaction was repeated, but with added
activated 3 Å molecular sieves. However, 3 and 5 were isolated
just as before. When the ethanol was replaced by 5 equiv of
freshly distilled n-butanol (which can be dried more effectively
than ethanol), the corresponding n-butyl sulfinate and sulfonate
25 and 26 were isolated in yields similar to those of the
respective ethyl esters 3 and 5 (Scheme 3), suggesting that no
prior hydrolysis of 1 by adventitious water is occurring.
Furthermore, 21, prepared independently,18 gave no 3 or 5, but
rather the corresponding disulfide 22 (80%) upon exposure to
m-CPBA in dichloromethane/ethanol at -15 °C. Disulfide 22
was also prepared independently and quantitatively (see the
(15) For a leading reference to S-glycosylsulfenic acids, see: Aversa,
M. C.; Barattucci, A.; Bilardo, M. C.; Bonaccorsi, P.; Giannetto, P.; Rollin,
P.; Tatiboue¨t, A. J. Org. Chem. 2005, 70, 7389-7396.
(16) (a) Gu, D.; Harpp, D. N. Tetrahedron Lett. 1993, 34, 67-70. (b)
Hartwig, U.; Rall, K.; Sundermeyer, W. Chem. Ber. 1990, 123, 595-598.
(c) Filby, W. G.; Gu¨nther, K.; Penzhorn, R. D. J. Org. Chem. 1973, 38,
4070-4071.
The deacetylated product 9 might arise at the higher reaction
temperature by interception of the nitrilium ion 11 by ethanol
(13) Khiar, N. Tetrahedron Lett. 2000, 41, 9059-9063.
(14) (a) Aucagne, V.; Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Gianneto, P.; Rollin, P.; Tatiboue¨t, A. J. Org. Chem. 2002, 67, 6925-
6930. (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.;
Giannetto, P.; Rollin, P. Lett. Org. Chem. 2004, 1, 376-380.
(17) (a) Jha, R.; Davis, J. T. Carbohydr. Res. 1995, 277, 125-134. (b)
Kusumoto, S.; Yamamoto, M.; Shiba, T. Tetrahedron Lett. 1984, 25, 3727-
3730. (c) Hanessian, S. Tetrahedron Lett. 1967, 1549-1552.
(18) Knapp, S.; Myers, D. S. J. Org. Chem. 2001, 66, 3636-3638.
1382 J. Org. Chem., Vol. 71, No. 4, 2006

New Glycomimetics
TABLE 1. Synthesis of 1-C-Sulfonates from
S-Acetyl-1-thiopyranosesa
Experimental Section) by treatment of 21 with iodine/pyridine,
and TLC comparisons of this material with the reaction products
of 1 with m-CPBA indicated that 22 was not formed, even as
a minor product. Interestingly, treatment of 21 under slightly
more forcing conditions (4 equiv of m-CPBA, -15 to 0 °C)
led to the isolation of substantial amounts of an additional (over-
oxidation) product, the unsymmetric anomeric thiolsulfonate
ester 23, in addition to 33% of 22. Independent m-CPBA
oxidation of 22 also produced 23. The NMR spectra of 23
feature signals from each of the two distinct R-GlcNAc units,
including respective anomeric C’s and H’s at 90.6/96.5 and 6.14/
5.39 ppm. While comparable m-CPBA oxidations have been
carried out on other symmetric dialkyl disulfides,19 thiolsulfonate
23 is, according to a Beilstein structure search, the first example
of a carbohydrate thiolsulfonate derivative with two anomeric
C-S bonds, and the dissimilar reactivity expected of these bonds
will be interesting to explore.
A report in the literature indicates that, in contrast to the
oxidation of 22, m-CPBA oxidation of S,S′-bis(2,3,4,6-tetra-O-
acetyl-â-D-glucopyranosyl) disulfide gives the thiolsulfinate
product (i.e., the mono-S-oxide) only.20 The formation of 23
from 21 or 22 ought to proceed through a thiosulfinate as well.
Treatment of 22 with 1.2 equiv of m-CPBA for 1 h at -10 °C
and then 5 h at 0 °C (reagent, time, and temperature must be
carefully limited) gave a mixture of three products (in order of
chromatographic elution): thiolsulfonate 23 (11%), starting
disulfide 22 (46%), and a new, low Rf product that proved to
be thiolsulfinate 24 (single diastereomer, 28%). The structure
of 24 was established by its mass spectrum, its NMR spectra,
which reveal the two distinct R-GlcNAc units with respective
anomeric C’s and H’s at 88.4/96.8 and 6.08/5.56 ppm, and its
independent m-CPBA oxidation at 23 °C to thiolsulfonate 23.
The apparent stereoselectivity of oxidation of 22 to 24 may again
be attributed to the exo-anomeric effect operating as for
thioglycosides,13,14 and so 24 can be analogously assigned the
R configuration at sulfur as shown (Scheme 3). Subjecting
mixtures containing both 22 and 24 to further m-CPBA oxidation
(more equiv and/or higher temperature) depletes 24 faster than
22. This implies that the second oxidation of the disulfide (to
give 23) is faster than the first, which is opposite to the usual
situation.21,22
Generalization of Anomeric Sulfonate Preparation. While
carbohydrate C-sulfonates at C-2, C-3, C-4, and C-6 of the
pyranose ring have been previously reported,23 the sulfinates
and sulfonates of Scheme 1 are, to our knowledge, the first
examples with this functionality at C-1. The anomeric carbon
is the most important linking position for natural glycoconjugates
of various types. Carbohydrate 1-C-sulfonates, thioglycosides
of a sort, may be thought of as potential enzyme-stable mimics24
of naturally occurring negatively charged carbohydrate sub-
structures such as O-phosphates, O-sulfates, neuraminidates, and
glycuronates. The potential of using sulfonates to mimic these
groups, or to otherwise interact with an electropositive group
in an active site, or to use for linking to other moieties, makes
them worthy of further exploration. Given also the specialized
nature of the reactions leading to sulfonates 7, 8, and, 9, it was
a Conditions: (1) DMDO, 0 °C, 12 h; (2) SiO2 chromatography with
CH2Cl2/MeOH/Et3N as the eluant.
of some interest to see whether the preparation of anomeric
C-sulfonic acids could be extended to 1-thio-D-glucopyranosyl
systems more generally.
We find that anomeric thioacetates (S-acetyl-1-thio-D-glu-
copyranoses), which are conveniently prepared by known
methods and can be stored without oxidation or decomposition,
are transformed directly to the anomeric sulfonic acids by the
action of dimethyldioxirane (DMDO). Each of the four anomeric
thioacetate substrates investigated (27-30, Table 1) was dis-
(23) (a) Sajtos, F.; La´za´r, L.; Borba´s, A.; Bajza, I.; Lipta´k, A. Tetrahedron
Lett. 2005, 46, 5191-5194. (b) Lipta´k, A.; Balla, E.; Ja´nossy, L.; Sajtos,
F.; Szila´gyi, L. Tetrahedron Lett. 2004, 45, 839-842. (c) Lipta´k, A.; Sajtos,
F.; Ja´nossy, L.; Gehle, D.; Szila´gyi, L. Org. Lett. 2003, 5, 3671-3674. (d)
Ferna´ndez-Bolan˜os, J. G.; Garc´ıa, S.; Ferna´ndez-Bolan˜os, J.; Dia´nez, M.
J.; Estrada, D.; Lo´pez-Castro, A.; Pe´rez-Garrido, S. Tetrahedron: Asymmetry
2003, 14, 3761-3768. (e) Ferna´ndez-Bolan˜os, J. G.; Ulgar, V.; Maya, I.;
Fuentes, J.; Dia´nez, M. J.; Estrada, M. D.; Lo´pez-Castro, A.; Pe´rez-Garrido,
S. Tetrahedron: Asymmetry 2003, 14, 1009-1018. (f) Hanashima, S.;
Mizushina, Y.; Yamazaki, T.; Ohta, K.; Takahashi, S.; Sahara, H.;
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2000, 41, 4403-4407. (h) Robina, I.; Go´mez-Bujedo, S.; Ferna´ndez-
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A. B.; Hewlins, M. J. E. Carbohydr. Res. 1997, 302, 113-117. (j)
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137-147. (k) Ferna´ndez-Bolan˜os, J. G.; Morales, J.; Garc´ıa, S.; Dia´nez,
M. J.; Estrada, M. D.; Lo´pez-Castro, A.; Pe´rez, S. Carbohydr. Res. 1993,
248, 1-14. (l) Gordon, D. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1992,
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I. M.; Guzman, J. F.-B. Carbohydr. Res. 1986, 147, 325-329. (q) Gigg,
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J. Org. Chem, Vol. 71, No. 4, 2006 1383

Knapp et al.
TABLE 2. Attempted Synthesis of Anomeric Sulfonyl Halidesa
SCHEME 4
of an oxocarbenium ion 42 (Scheme 4). Kinetic addition of
fluoride ion to the R- and â-face of 42, without subsequent
equilibration, could account for formation of the product 37 of
the DAST reaction as the mixture of anomeric fluorides.33 In
contrast, equilibration of possible anomeric chloride kinetic
mixtures derived from 42 to the more stable respective R-ano-
mers 35 and 36 might be expected to occur under these
conditions.34
a Reactions were run in CH2Cl2 solution at 0-23 °C for 2 h.
Sulfonic acids 32 and 33 were also treated with various
peptide coupling reagents, including N-(3-dimethylaminopro-
pyl)-N′-ethylcarbodiimide, 2-chloro-4,6-dimethoxy-1,3,5-triaz-
ine, and DCC/1-hydroxybenzotriazole, to activate the sulfonyl
group. Attempted couplings in DMF solution with benzylamine
present as the nucleophile, however, led only to the recovery
of starting sulfonic acid.
solved in a solution of DMDO25 in acetone at 0 °C and allowed
to react for a 12 h period.26 The solution was simply concen-
trated and chromatographed with an eluant containing triethyl-
amine to afford the sulfonic acid as the triethylammonium salt.
The 1H and 13C NMR spectra as well as the negative ion mass
spectrum of each product confirm its identity.
Synthesis of R- and â-GlcNAc Sulfenamides. Sulfen-
amides35 can serve, through oxidation at sulfur, as precursors
to sulfonamides. The R-GlcNAc mercaptan 21 was therefore
treated with sulfuryl chloride36 to generate a presumed inter-
mediate sulfenyl chloride 43 (Scheme 5), and then 1 equiv of
diethylamine, as a prototypical nucleophilic amine, was added
along with Hu¨nig’s base in order to neutralize the acid formed.
The desired N,N-diethylsulfenamide 44 was isolated in 58%
yield.37 Somewhat better efficiency was obtained by bromina-
tion38 of 21 at -78 °C, presumably by way of the corresponding
sulfenyl bromide. Deprotection of 44 to the R-GlcNAc sulfen-
amide triol 45 was achieved under Zemple´n conditions.
Analogous treatment of the â-GlcNAc mercaptan39 46 gave the
corresponding N,N-diethylsulfenamide 47, but the yield was low.
However, bromination40 of the â-GlcNAc thioacetate 27
proceeded more efficiently, and analogous deprotection to the
â-GlcNAc sulfenamide triol 48 was also successful.
Attempted Synthesis of Anomeric Sulfonyl Chlorides and
Sulfonamides. An unusual enzyme-resistant replacement for
the glycosidic linkage in neoglycoconjugates would be the
sulfonamide27,28 corresponding to the union of an anomeric
sulfonic acid (e.g., 7, 31-34) and an amine.29 We therefore
invested some effort (see Table 2) in trying to activate anomeric
sulfonates as the corresponding sulfonyl halide, either chloride
or fluoride. For example, treatment of an anomeric sulfonate
as its triethylamine salt (32 or 33) with PCl5 or POCl3, standard
reagents for the formation of sulfonic acid chlorides, led only
to the corresponding known R-anomeric chlorides (35 and 36,
respectively, Table 2). Attempted conversion of 32 to the
sulfonic acid fluoride with diethylaminosulfur trifluoride
(DAST)30,31 gave instead the known anomeric fluorides 37.
Reaction of 32 with oxalyl chloride or with triphenylphosphine
and sulfuryl chloride32 likewise gave only 35. Evidently, the
anomeric C-sulfonyl chloride 39, if formed, is unstable toward
loss of SO2, or else halide anion intercepts an activated sulfonic
mixed anhydride 41 at the anomeric carbon, possibly by way
(33) Griffith, M. H. E.; Hindsgaul, O. Carbohydr. Res. 1991, 211, 163-
166.
(34) Ernst, B.; Winkler, T. Tetrahedron Lett. 1989, 30, 3081-3084.
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G.; Modena, G.; Pasquato, L. In The Chemistry of Sulfenic Acids and Their
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Craine, L.; Raban, M. Chem. ReV. 1989, 89, 689-712.
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(37) Other S-glycosyl sulfenamides: (a) Illye´s, T.-Z.; Molna´r-Ga´bor, D.;
Szila´gyi, L. Carbohydr. Res. 2004, 339, 1561-1564. (b) Owen, D. J.; von
Itzstein, M. Carbohydr. Res. 2000, 328, 287-292. (c) Hu¨rzeler, M.; Bernet,
B.; Vasella, A. HelV. Chim. Acta 1992, 75, 557-588. (d) Bell, R. H.; Horton,
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(25) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.
(26) Oxidation of thioacetates with H2O2 and acetic acid has been
reported: Ulgar, V.; Maya, I.; Fuentes, J.; Ferna´ndez-Bolan˜os, J. Tetrahe-
dron 2002, 58, 7967-7973 and references therein.
(27) Johnson, D. C., II; Widlanski, T. S. Tetrahedron Lett. 2004, 45,
8483-8487 and references therein.
(28) Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D.
B. Org. Lett. 2002, 4, 2549-2551.
(29) N-Glycosyl sulfonamides have also been reported: Colinas, P. A.;
Bravo, R. D. Tetrahedron Lett. 2005, 46, 1687-1689.
(30) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561-2578.
(31) Segall, Y.; Quistad, G. B.; Casida, J. E. Synth. Commun. 2003, 33,
2151-2159.
(38) Kharasch, N.; Bruice, T. C. J. Am. Chem. Soc. 1951, 73, 3240-
3244.
(39) Meyer zu Reckendorf, W.; Bonner, W. A. J. Org. Chem. 1961, 26,
4596-4599.
(32) Huang, J.; Widlanski, T. S. Tetrahedron Lett. 1992, 33, 2657-2660.
1384 J. Org. Chem., Vol. 71, No. 4, 2006

New Glycomimetics
SCHEME 5
carbohydrate processing enzymes such as N-acetylhexosamini-
dases or glucosyl transferases. The unnatural functionality ought
to make them nonprocessable as substrates, so they and related
compounds may ultimately have value as enzyme inhibitors,
or as enzyme resistant components of vaccines, biomimetic
probes, and other neoglycoconjugates.
Experimental Section
(3aR,5R,6S,7R,7aR)-5-Phenylmethoxymethyl-6,7-bis(phenyl-
methoxy)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thia-
zole (2). A mixture of 212 µL (1.78 mmol) of benzyl bromide, 66
mg (1.66 mmol of a 60% dispersion in mineral oil) of sodium
hydride, and 6 mL of DMF was treated at 0 °C (bath temperature)
with 110 mg (0.502 mmol) of GlcNAc-thiazoline triol (prepared
from 1 by methanolysis18) in 4 mL of DMF. The reaction was
allowed to warm to 23 °C over 4 h and then was concentrated and
chromatographed on silica with 1:3 ethyl acetate/hexanes as the
eluant to provide 218 mg (98%) of 2 as a colorless oil, Rf 0.37
(3:7 ethyl acetate/hexanes): 1H NMR (300 MHz, CDCl3) δ 7.23-
7.42 (m, 13 H), 7.15-7.21 (m, 2 H), 6.35 (d, 1 H, J ) 9.2 Hz),
4.72 and 4.64 (ABq, 2 H, J ) 12.0 Hz), 4.53 and 4.24 (ABq, 2 H,
J ) 11.6), 4.46-4.58 (obscured m, 1 H), 4.51 and 4.46 (ABq, 2
H, J ) 12.3), 4.34 (br t, 1 H, J ) 1.8 Hz), 3.68 (br d, 1 H, J ) 8.7
Hz), 3.40-3.58 (m, 3 H), 2.28 (d, 3 H, J ) 2.1 Hz); 13C NMR (75
MHz, CDCl3) δ 167.2, 138.3, 138.1, 137.9, 128.7, 128.49, 128.47,
128.3, 128.2, 128.1, 128.0, 127.97, 127.7, 89.6, 78.1, 76.4, 76.2,
73.4, 71.9 (2 C), 71.5, 70.0, 21.0; FAB-MS m/z 490 MH+.
SCHEME 6
(2R,3S,4R,5R,6R)-5-Acetamido-2-(acetoxymethyl)-6-(ethoxy-
sulfinyl)tetrahydro-2H-pyran-3,4-diylDiacetate(3)and(2R,3S,4R,5R,6R)-
5-Acetamido-2-(acetoxymethyl)-6-(ethoxysulfonyl)tetrahydro-
2H-pyran-3,4-diyl Diacetate (5). A solution of 46.2 mg (0.134
mmol) of 1 in 3 mL of dichloromethane was cooled to -17 °C
(bath temperature) and maintained between -15 and -20 °C.
Ethanol (39 µL, 0.670 mmol) was added, followed by 92 mg (0.536
mmol) of buffer-washed m-CPBA. The reaction was stirred at -15
to -20 °C for 0.5 h, and then the reaction mixture was quenched
by addition of aqueous sodium sulfite and sodium bicarbonate. The
organic layer was dried over anhydrous magnesium sulfate and then
concentrated to a residue. Chromatography on silica with 3:7 ethyl
acetate/dichloromethane as the eluant afforded 22 mg (38%) of
sulfonate ester 5 as a colorless oil, Rf 0.47 (3:7 ethyl acetate/
dichloromethane), and 20 mg (35%) of sulfinate ester 3 as a
colorless oil, Rf 0.26 (3:7 ethyl acetate/dichloromethane). Data for
5: 1H NMR (300 MHz, CDCl3) δ 6.18 (d, 1 H, J ) 7.6 Hz), 5.65
(dd, 1 H, J ) 11.2, 9.2 Hz), 5.35 (d, 1 H, J ) 6.3 Hz), 5.17 (t, 1
H, J ) 9.6 Hz), 4.58 (ddd, 1 H, J ) 9.2, 7.6, 6.0 Hz), 4.34 (q, 2
H, J ) 7.2 Hz), 4.29-4.39 (partially obscured 1 H), 4.21 (dd, 1 H,
J ) 12.8, 4.4 Hz), 4.13 (dd, 1 H, J ) 12.8, 2.4 Hz), 2.08, 2.05,
2.04, 1.98 (4 s, 3 H each), 1.41 (t, 3 H, J ) 9.6 Hz); 13C NMR (75
MHz, CDCl3) δ 171.1, 170.9, 170.2, 169.0, 86.1, 72.7, 69.5, 69.1,
67.1, 61.6, 50.6, 23.0, 20.7, 20.7, 20.6, 15.1; FAB-MS m/z 446
MLi+. Data for 3: 1H NMR (300 MHz, CDCl3) δ 6.43 (d, 1 H, J
) 8.4 Hz), 5.58 (dd, 1 H, J ) 10.5, 9.0 Hz), 5.11 (t, 1 H, J ) 9.3
Hz), 4.74 (d, 1 H, J ) 5.7 Hz), 4.66-4.74 (obscd ddd, 1 H), 4.04-
4.19 (m, 5 H), 2.04, 1.99, 1.98, 1.91 (4 s, 3 H each), 1.34 (t, 3 H,
J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 171.2, 170.7, 170.6,
169.4, 92.6, 73.9, 70.6, 68.2, 66.9, 61.9, 51.2, 23.3, 20.9, 20.85,
20.76, 16.1; FAB-MS m/z 430 MLi+, 424 MH+.
Oxidation of sulfenamide 44 with 2.4 equiv of m-CPBA41 at
23 °C did not give the corresponding sulfonamide, but rather
the (mono-oxidized42) sulfinamide 49 as a single isomer in good
yield (Scheme 6). Again, the stereoselectivity of the 1-thio-R-
D-glucopyranoside oxidation may reflect the exo-anomeric
effect13,14 on sulfenamide conformation, presumably leading to
the S stereoisomer at sulfur (shown). Resubjecting the 49 to 2
equiv of m-CPBA, but at 40 °C instead, gave the sulfonamide
50 quantitatively. Deacetylation as before provided the sulfon-
amide triol 51.
The R-GlcNAc sulfonate 8, sulfenamides 45 and 48, and
sulfonamide 51 possess atypical functionality at the pyranose
anomeric center, where they might interact with active sites of
(40) Boehme, H.; Steudel, H. P. Justus Liebigs Ann. Chem. 1969, 730,
121-132.
(41) (a) Garc´ıa Mart´ınez, A.; Teso Villar, E.; Moreno Jime´nez, F.; Garc´ıa
Amo, M. Tetrahedron: Asymmetry 2000, 11, 1709. (b) Refvik, M. D.;
Schwan, A. L. J. Org. Chem. 1996, 61, 4232-4239. (c) Schwan, A. L.;
Refvik, M. D. J. Chem. Soc., Chem. Commun. 1995, 1949-1950. (d) Glass,
R. S.; Swedo, R. J. Synthesis 1977, 798-800.
(42) (a) Merricks, D.; Sammes, P. G.; Walker, E. R. H.; Henrick, K.;
McPartlin, M. M. J. Chem. Soc., Perkin Trans. 1 1991, 2169-2176. (b)
Harpp, D. N.; Mullins, D. F.; Steliou, K.; Triassi, I. J. Org. Chem. 1979,
44, 4196-4197.
The ethyl sulfonate 5 was also obtained by independent oxidation
of sulfinate 3 as follows. A solution of 18 mg (0.043 mmol) of 3
in 0.8 mL in dichloromethane was cooled to 0 °C bath temperature
and treated with 18 mg (0.106 mmol) of m-CPBA. The reaction
mixture was allowed to warm to room temperature and stir for 1
h. The reaction was quenched with a 5% sodium bicarbonate/
saturated aqueous sodium sulfite solution at 0 °C and allowed to
warm to room temperature. The organic layer was separated, dried,
concentrated, and then chromatographed on silica with 3:1 dichlo-
J. Org. Chem, Vol. 71, No. 4, 2006 1385

Knapp et al.
romethane/ethyl acetate as the eluant to give 17.1 mg (91%) of 5
as a colorless oil, Rf 0.47 (7:3 dichloromethane/ethyl acetate). The
1H NMR and FAB mass spectra matched those obtained previously
for 5.
mmol) of acetic anhydride in 1 mL of pyridine was stirred for 16
h. The solution was concentrated and then chromatographed on
silica with 96:2:2 dichloromethane/methanol/triethylamine as the
eluant to give 42.3 mg (86%) of 7 as a light brown oil, Rf 0.2 (96:
2:2 dichloromethane/methanol/triethylamine). The 1H NMR spec-
trum and TLC behavior matched that of 7 as prepared above.
(2R,3R,4R,5S,6R)-3-Acetamido-4,5-dihydroxy-6-(hydroxy-
methyl)tetrahydro-2H-pyran-2-sulfonic Acid (8). Sodium meth-
oxide (10 µL of a 1 M methanol solution, 0.01 mmol) was added
to a solution of 42 mg (0.082 mmol) of 7 in 1 mL of methanol at
0 °C. The reaction was allowed to stir for 1 h, concentrated, and
then chromatographed with methanol through a Sephadex G-25 plug
to give 23 mg (98%) of 8 as a colorless oil: 1H NMR (300 MHz,
D2O) δ 4.71 (d, 1 H, J ) 6.3 Hz), 4.10 (dd, 1 H, J ) 10.8, 8.4
Hz), 4.02 (dd, 1 H, J ) 10.8, 6.3 Hz), 3.89 (ddd, 1 H, J ) 10.2,
3.9, 2.1 Hz), 3.72 (dd, 1 H, J ) 12.3, 2.1 Hz), 3.64 (dd, 1 H, J )
12.6, 4.2 Hz), 3.39 (t, 1 H, J ) 10 Hz), 1.89 (s, 3 H); 13C NMR
(75 MHz, D2O) δ 174.9, 85.2, 75.8, 70.0, 69.9, 60.0, 52.1, 22.2;
NI-FAB-MS m/z 274 M-.
A high-yield preparation of 5 from 1 was also carried out, as
follows. A solution of 115 mg (0.333 mmol) of 1 in 6.0 mL of
dichloromethane was cooled to -15 °C bath temperature and treated
with 97.0 µL (1.67 mmol) of ethanol. m-CPBA (229 mg, 1.33
mmol) was added and the reaction mixture was stirred at -10 °C
for 2 h and then allowed to warm to room temperature and stir for
1 h. The reaction was quenched with a 5% sodium bicarbonate/
saturated aqueous sodium sulfite solution at 0 °C and allowed to
warm to room temperature. The organic layer was separated, dried,
concentrated, and then chromatographed on silica with 3:1 dichlo-
romethane/ethyl acetate as the eluant to give 123 mg (84%) of 5
as a colorless oil, Rf 0.47 (7:3 dichloromethane/ethyl acetate). The
1H NMR and FAB mass spectra matched those obtained previously
for 5.
Ethyl (2R,3R,4R,5S,6R)-3-Acetamido-4,5-bis(benzyloxy)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-sulfinate (4) and Eth-
yl (2R,3R,4R,5S,6R)-3-Acetamido-4,5-bis(benzyloxy)-6-(benzyl-
oxymethyl)tetrahydro-2H-pyran-2-sulfonate (6). Ethanol (140
µL, 2.40 mmol) and 330 mg (1.91 mmol) of m-CPBA were added
to a cooled solution of 231.2 mg (0.479 mmol) of 2 in 2 mL of
dichloromethane, maintained between -15 and -20 °C bath
temperature. The reaction mixture was stirred at that temperature
for 0.5 h and then was quenched by addition of aqueous sodium
sulfite and sodium bicarbonate. The organic layer was dried with
anhydrous magnesium sulfate, concentrated, and then chromato-
graphed on silica with 1:4 ethyl acetate/dichloromethane as the
eluant to afford 84 mg (30%) of 6 as a colorless oil, Rf 0.4 (3:7
ethyl acetate/hexanes), and 76 mg (28%) of 4 as a colorless oil, Rf
0.27 (3:7 ethyl acetate/hexanes). Data for 6: 1H NMR (300 MHz,
CDCl3) δ 7.20-7.25 (m, 15 H), 5.32 (d, 1 H, J ) 7.8 Hz), 5.27 (d,
1 H, J ) 5.7 Hz), 4.83 (d, 1 H, J ) 12.0 Hz), 4.78 (d, 1 H, J )
11.1 Hz), 4.64 (d, 1 H, J ) 12.0 Hz), 4.59 (d, 1 H, J ) 12.3 Hz),
4.58 (d, 1 H, J ) 11.1 Hz), 4.49 (d, 1 H, J ) 12.3 Hz), 4.42-4.50
(partially obscured ddd, 1 H), 4.30 (q, 2 H, J ) 7.2 Hz), 4.21 (ddd,
1 H, J ) 8.4, 4.8, 2.7 Hz), 3.77 (dd, 1 H, J ) 11.1, 4.8 Hz), 3.71
(t, 1 H, J ) 8.4 Hz), 3.69 (dd, 1 H, J ) 11.1, 2.7), 1.75 (s, 3 H),
1.32 (t, 3 H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 170.6,
137.9, 137.7, 128.9, 128.7, 128.6, 128.5, 128.4, 128.1, 127.9, 87.3,
77.4, 76.5, 74.9, 73.7, 69.3, 68.2, 50.4, 23.3, 15.4; FAB-MS m/z
590 MLi+. Data for 4: 1H NMR (300 MHz, CDCl3) δ 7.19-7.25
(m, 15 H), 5.33 (d, 1 H, J ) 7.9 Hz), 4.69 (d, 1 H, J ) 5.5 Hz),
4.46-4.82 (m, 7 H), 4.01-4.27 (m, 3 H), 4.05 (dd, 1 H, J ) 9.8,
8.5 Hz), 3.58-3.66 (m, 3 H), 1.77 (s, 3 H), 1.33 (t, 3 H, J ) 6.8
Hz); 13C NMR (75 MHz, CDCl3) δ 171.2, 170.7, 170.6, 169.4,
92.6, 73.9, 70.6, 68.2, 66.9, 61.9, 51.2, 23.3, 20.9, 20.85, 20.76,
16.1; FAB-MS m/z 574 MLi+, 568 MH+.
Triethylammonium (2R,3R,4R,5S,6R)-3-Acetamido-4,5-diac-
etoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-sulfonate (7). A
solution of 42.2 mg (0.096 mmol) of 5 and 16 µL (0.107 mmol) of
1,8-diazabicyclo[5.4.0]undec-7-ene in 1 mL of toluene was heated
at 55 °C for 0.5 h. The solution was concentrated and chromato-
graphed on silica with 96:2:2 dichloromethane/methanol/triethyl-
amine as the eluant to give 42.3 mg (86%) of 7 as a light brown
oil, Rf 0.2 (96:2:2 dichloromethane/methanol/triethylamine): 1H
NMR (300 MHz, CDCl3) δ 9.82 (br s, 1 H), 6.63 (d, 1 H, J ) 9.6
Hz), 5.76 (dd, 1 H, J ) 10.8, 9.2 Hz), 5.11 (t, 1 H, J ) 9.2 Hz),
4.64 (d, 1 H, J ) 6.0 Hz), 4.60-4.67 (m, 1 H), 4.54 (ddd, 1 H, J
) 10.8, 9.6, 6.0 Hz), 4.12 (dd, 1 H, J ) 12.8, 3.6 Hz), 4.06 (dd, 1
H, J ) 12.8, 2.4 Hz), 3.07 (q, 6 H, J ) 7.2 Hz), 1.99, 1.91, 1.90,
1.85 (4 s, 3 H each), 1.29 (t, 9 H, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 170.9, 170.8, 170.4, 169.4, 85.6, 71.3, 71.1, 68.6,
62.3, 50.1, 46.6 (3 C), 23.7, 21.1, 21.1, 20.9, 9.9 (3 C); NI-FAB-
MS m/z 410 M-.
(2R,3R,4R,5S,6R)-4,5-Diacetoxy-6-(acetoxymethyl)-3-aminotet-
rahydro-2H-pyran-2-sulfonic Acid (9). Ethanol (88 µL, 1.51
mmol) and 208 mg (1.21 mmol) of m-CPBA were sequentially
added to a solution of 104.2 mg (0.302 mmol) of 1 in 2 mL of
dichloromethane at 23 °C. After 30 min, the reaction mixture was
concentrated and then chromatographed on silica with 1:19
methanol/dichloromethane as the eluant to give 30 mg (23%) of 5
and then 48 mg (43%) of the amino sulfonic acid 9 as a colorless
oil, Rf 0.2 (1:19 methanol dichloromethane): 1H NMR (300 MHz,
D2O) δ 5.82 (dd, 1 H, J ) 9.9, 8.1 Hz), 5.49 (dd, 1 H, J ) 9.3, 8.1
Hz), 5.07 (d, 1 H, J ) 5.4 Hz), 4.65-4.72 (m, 1 H), 4.42 (dd, 1 H,
J ) 12.8, 3.6 Hz), 4.24 (dd, 1 H, J ) 12.6, 2.1 Hz), 4.01 (dd, 1 H,
J ) 9.0, 5.4 Hz), 2.15, 2.12, 2.10 (3 s, 3 H each); 13C NMR (75
MHz, D2O) δ 173.7, 172.9, 172.7, 82.8, 72.0, 69.7, 68.5, 61.9, 49.6,
20.5, 20.4, 20.4; FAB-MS m/z 370 MH+.
S,S′-Bis(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopy-
ranosyl) Disulfide (22). Iodine (66 µL of a 0.79 M solution in
THF, 0.052 mmol) was added in aliquots over a 15 min period to
a solution of 32 mg (0.088 mmol) of 21 in 0.75 mL of THF and
14 µL (0.176 mmol) of pyridine at 0 °C, whereupon a white
precipitate formed and an orange color persisted. The reaction
mixture was concentrated and then chromatographed on silica with
ethyl acetate as the eluant to afford 32 mg (100%) of 22 as a white
solid, mp (sealed capillary) 110-112 °C (change in crystal
morphology), then 176-178 °C (melt), Rf 0.30 (ethyl acetate): 1H
NMR (400 MHz, CDCl3) δ 5.91 (d, 2 H, J ) 8.4 Hz), 5.41 (d, 2
H, J ) 5.2 Hz), 5.14 (t, 2 H, J ) 9.6 Hz), 5.04 (dd, 2 H, J ) 9.6,
11.6 Hz), 4.47 (ddd, 2 H, J ) 5.2, 8.6, 11.2 Hz), 4.25 (dd, 2 H, J
) 4.0, 12.0 Hz), 4.19-4.09 (m, 4 H), 2.09 (s, 6 H), 2.04 (s, 6 H),
2.03 (s, 6 H), 1.97 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 171.9,
170.8, 170.3, 169.3, 91.7, 71.0, 70.2, 67.7, 61.5, 53.2, 23.2, 20.85,
20.81, 20.7; FAB-MS m/z 747 MNa+.
S-(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopyrano-
syl) 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopyranosyl-
1-C-thiosulfonate (23). A solution of 63.7 mg (0.175 mmol) of
2-acetamido-2-deoxy-1-thio-3,4,6-tri-O-acetyl-R-D-glucopyranose
21 in 3.5 mL of dichloromethane was cooled to -15 °C bath
temperature and treated with 51.0 µL (0.875 mmol) of ethanol.
m-CPBA (120 mg, 0.700 mmol) was added, and the reaction
mixture was stirred at 0 °C for 0.5 h. The reaction was quenched
with a 5% sodium bicarbonate/saturated aqueous sodium sulfite
solution at 0 °C and allowed to warm to room temperature. The
organic layer was separated, dried, and concentrated, and then the
crude product was chromatographed on silica with 4:1 ethyl acetate/
dichloromethane as the eluant to give 24.9 mg (38%) of 23 as a
colorless oil, Rf 0.38 (ethyl acetate), and also 20.8 mg (33%) of
the previously described disulfide 22. Data for 23: 1H NMR (400
MHz, CDCl3) δ 6.19 (δ, 1 H, J ) 7.6 Hz), 6.14 (d, 1 H, J ) 5.2
Hz), 5.80 (d, 1 H, J ) 7.8 Hz), 5.62 (dd, 1 H, J ) 9.3, 10.8 Hz),
5.39 (d, 1 H, J ) 6.0 Hz), 5.20 and 5.17 (overlapping t’s, 2 H, J
Sulfonate 7 was also prepared by acetylating 9 as follows. A
solution of 24 mg (0.065 mmol) of 9 (see below) and 7.4 µL (0.078
1386 J. Org. Chem., Vol. 71, No. 4, 2006

New Glycomimetics
) 9.6 and 9.3 Hz respectively), 4.82 (dd, 1 H, J ) 9.3, 11.7 Hz),
4.70-4.56 (m, 2 H), 4.38-4.02 (m, 6 H), 2.12 (s, 3 H), 2.11 (s, 3
H), 2.07 (s, 3 H), 2.06 (s, 6 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.99
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 172.0, 171.8, 171.1,
170.72, 170.68, 170.4, 169.3, 169.2, 96.5, 90.6, 74.1, 72.2, 71.3,
69.8, 67.1, 66.8, 61.5, 61.2, 52.9, 52.1, 23.4, 23.2, 20.9, 20.85,
20.84, 20.83, 20.74, 20.72; FAB-MS m/z 779 MNa+.
An otherwise identical oxidation reaction of 21 run instead with
2.5 equiv of m-CPBA at -15 °C for 30 min gave no 23, but rather
the disulfide 22 in 80% yield, as determined by comparison to
authentic material.
) 10.8, 9.2, 6.0 Hz), 4.06-4.31 (m, 5 H), 2.11, 2.05, 2.05, 1.97 (4
s, 3 H each), 1.72 (quint, 2 H, J ) 7.2 Hz), 1.42 (sext, 2 H, J )
7.4 Hz), 0.98 (t, 3 H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
170.9, 170.5, 170.4, 169.2, 92.4, 73.6, 70.6, 68.0, 62.2, 61.8, 54.9,
51.9, 32.0, 23.1, 20.7, 20.6, 18.7, 13.6; FAB-MS m/z 474 MNa+,
452 MH+.
Triethylammonium (2S,3R,4R,5S,6R)-3-Acetamido-4,5-diac-
etoxy-6-(acetoxymethyl)-tetrahydro-2H-pyran-2-sulfonate (31).
Dimethyldioxirane (3.7 mL of a 0.079 M solution in acetone) was
added to a flask containing a solution of 30 mg (0.740 mmol) of
thioacetate 2743 in 1 mL of acetone at 0 °C. The solution was stirred
at 0 °C for 12 h, then concentrated and chromatographed on silica
with 97:2:1 dichloromethane/methanol/triethylamine as the eluant
to give 31 mg (82%) of 31, Rf 0.2 (97:2:1 dichloromethane/
methanol/triethylamine): 1H NMR (300 MHz, CDCl3) δ 6.47 (d,
1 H, J ) 8.4 Hz), 5.36 (d, 1 H, J ) 9.6 Hz), 5.09 (t, 1 H, J ) 9.9
Hz), 4.51 (d, 1 H, J ) 10.2 Hz), 4.23-4.34 (m, 2 H), 4.09 (dd, 1
H, J ) 12.6, 2.1 Hz), 3.81 (ddd, 1 H, J ) 9.9, 4.2, 2.1 Hz), 3.06
(q, 1 H, J ) 7.5 Hz), 2.02, 1.99, 1.98, 1.90 (4 s, 3 H each), 1.31,
(t, 1 H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 170.9, 170.8,
170.7, 169.7, 86.3, 76.1, 74., 68.8, 62.6, 52.2, 46.4, 23.8, 21.3, 21.0,
9.3; NI-FAB-MS m/z 410 M-.
Triethylammonium (2S,3R,4S,5R,6R)-3,4,5-Triacetoxy-6-(ac-
etoxymethyl)tetrahydro-2H-pyran-2-sulfonate (32). Dimethyl-
dioxirane (8 mL of a 0.070 M solution in acetone) was added to a
flask containing a solution of 66 mg (0.16 mmol) of thioacetate
2844 in 1 mL of acetone at 0 °C. The solution was stirred at 0 °C
for 12 h, concentrated, and then chromatographed on silica with
98:1:1 dichloromethane/methanol/triethylamine as the eluant to give
73 mg (87%) of 32, Rf 0.2 (98:1:1 dichloromethane/methanol/
triethylamine): 1H NMR (300 MHz, CDCl3) δ 5.40 (t, 1 H, J )
9.6 Hz), 5.22 (t, 1 H, J ) 9.6 Hz), 5.08 (t, 1 H, J ) 9.9 Hz), 4.30
(dd, 1 H, J ) 12.6, 4.8 Hz), 4.24 (d, 1 H, J ) 9.9 Hz), 4.08 (dd,
1 H, J ) 12.6, 2.1 Hz), 3.74 (ddd, 1 H, J ) 9.9, 4.8, 2.1 Hz), 2.86
(q, 6 H, J ) 7.5 Hz), 1.99, 1.98, 1.96, 1.94 (4 s, 3 H each), 1.18
(t, 9 H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 171.0, 170.6,
170.5, 169.2, 92.6, 73.9, 70.6, 68.2, 66.9, 62.0, 51.3, 23.4, 21.0,
20.9, 16.3; NI-FAB-MS m/z 411 M-.
Thiosulfonate23 was also prepared from the thiosulfinate 24 (see
below) as proof of structure. m-CPBA (1.5 mg, 8.72 µmol) was
added to a solution of 2.9 mg (3.92 µmol) of thiosulfinate 24 in
0.75 mL of dichloromethane at 0 °C. The mixture was stirred at
23 °C for 4 h, whereupon TLC indicated the complete consumption
of the starting material and the appearance of a single new product
1
with higher Rf. The TLC behavior, H NMR spectrum, and FAB-
MS of the product matched those of 23.
S-(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopyrano-
syl) 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopyranosyl-
1-C-thiosulfinate (24). m-CPBA (11 mg, 0.066 mmol) was added
to a solution of 40 mg (0.055 mmol) of disulfide 22 in 1.5 mL of
dichloromethane at -15 °C bath temperature. The mixture was
stirred at -10 °C for 1 h and then allowed to warm to 0 °C and to
stir for 5 h. The reaction was quenched with a 5% sodium
bicarbonate/saturated aqueous sodium sulfite solution at 0 °C and
allowed to warm to room temperature. The organic layer was
separated, dried, concentrated, and then chromatographed on silica
with 4:1 dichloromethane/tetrahydrofuran as the eluant to give in
order of elution 4.6 mg (11%) of the previously described
thiosulfonate 23, 18.3 mg (46%) of the disulfide 21, and 11.4 mg
(28%) of the thiosulfinate 24 as a single diastereomer, Rf 0.26 (ethyl
acetate). Data for 24: 1H NMR (400 MHz, CDCl3) δ 6.58 (d, 1 H,
J ) 8.4 Hz), 6.08 (d, 1 H, J ) 4.8 Hz), 5.87 (d, 1 H, J ) 7.6 Hz),
5.72 (app t, 1 H, J ) 9.2 Hz), 5.56 (d, 1 H, J ) 6.0 Hz), 5.21 and
5.19 (overlapping t’s, 2 H, J ) 9.6 Hz), 5.00 (dd, 1 H, J ) 9.6,
11.2 Hz), 4.85 (ddd, 1 H, J ) 6.4, 8.4, 10.8 Hz) 4.60 (ddd, 1 H, J
) 4.8, 7.6, 11.6 Hz), 4.30-3.94 (m, 6 H), 2.10 (s, 6 H), 2.08 (s, 6
H), 2.06 (s, 6 H), 2.05 (s, 3 H), 2.00 (s, 3 H); 13C NMR δ 172.1,
171.3, 171.0, 170.7, 170.6 (2 C’s), 169.4, 169.2, 96.8, 88.4, 73.6,
71.7, 71.0, 70.3, 67.8, 67.4, 61.7, 61.6, 53.4, 52.2, 23.5, 23.4, 20.9
(2 C’s), 20.85 (2 C’s), 20.7 (2 C’s); FAB-MS m/z 763 MNa+.
n-Butyl 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-R-D-glucopy-
ranosyl-1-C-sulfinate (25) and n-Butyl 2-Acetamido-2-deoxy-
3,4,6-tri-O-acetyl-R-D-glucopyranosyl-1-C-sulfonate (26). n-Bu-
tanol (70 µL, 0.761 mmol) and 105 mg (0.609 mmol) of m-CPBA
were added to a cooled solution of 52.5 mg (0.152 mmol) of 1 in
2 mL of dichloromethane, maintained between -15 and -20 °C
bath temperature. The reaction mixture was stirred at that temper-
ature for 0.5 h, then was quenched by addition of aqueous sodium
sulfite and sodium bicarbonate. The organic layer was dried with
anhydrous magnesium sulfate, concentrated, and then chromato-
graphed on silica with 15:85 ethyl acetate/dichloromethane as the
eluant to give 31 mg (43%) of 26 as a colorless oil, Rf 0.62 (3:7
ethyl acetate/dichloromethane), and 23 mg (34%) of 25 as a
colorless oil, Rf 0.34 (3:7 ethyl acetate/dichloromethane). Data for
26: 1H NMR (400 MHz, CDCl3) δ 6.16 (d, 1 H, J ) 8.0 Hz), 5.66
(dd, 1 H, J ) 11.2, 9.2 Hz), 5.36 (d, 1 H, J ) 6.4 Hz), 5.18 (t, 1
H, J ) 9.6 Hz), 4.59 (ddd, 1 H, J ) 11.2, 8.0, 6.4 Hz), 4.38 (ddd,
1 H, J ) 8.0, 4.0, 2.0 Hz), 4.29 (t, 2 H, J ) 6.4 Hz), 4.24 (dd, 1
H, J ) 12.8, 4.0 Hz), 4.13 (d, 1 H, J ) 12.8 Hz), 2.10, 2.06, 2.05,
1.99 (4 s, 3 H each), 1.72 (quint, 2 H, J ) 7.2 Hz), 1.42 (sext, 2
H, J ) 6.8 Hz), 0.98 (t, 3 H, J ) 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 171.4, 171.1, 170.4, 169.2, 86.2, 72.8, 72.7, 69.6, 67.1,
61.5, 50.6, 31.1, 23.0, 20.7, 20.6, 20.5, 18.5, 13.4; FAB-MS m/z
490 MNa+, 468 MH+. Data for 25: 1H NMR (400 MHz, CDCl3)
δ 6.14 (d, 1 H, J ) 8.8 Hz), 5.64 (dd, 1 H, J ) 10.8, 9.6 Hz), 5.18
(t, 1 H, J ) 9.6 Hz), 4.83 (d, 1 H, J ) 5.6 Hz), 4.76 (ddd, 1 H, J
Triethylammonium (2S,3R,4S,5S,6R)-3,4,5-Tris(benzyloxy)-
6-(benzyloxymethyl)tetrahydro-2H-pyran-2-sulfonate (33). Di-
methyldioxirane (18 mL of a 0.079 M solution in acetone) was
added to a flask containing a solution of 249 mg (0.415 mmol) of
thioacetate 2945 in 1 mL of acetone at 0 °C. The solution was stirred
at 0 °C for 12 h, concentrated, and then chromatographed on silica
with 198:1:1 dichloromethane/methanol/triethylamine as the eluant
to give 242 mg (82%) of 33, Rf 0.4 (98:1:1 dichloromethane/
methanol/triethylamine): 1H NMR (300 MHz, CDCl3) δ 7.15-
7.50 (m, 15 H), 5.24 (d, 1 H, J ) 9.9 Hz), 5.00 (d, 1 H, J ) 11.1
Hz), 4.85 (app dd, 2 H, J ) 11.1, 11.4 Hz), 4.70 (d, 1 H, J ) 9.6
Hz), 4.57 (d, 1 H, J ) 10.8 Hz), 4.48, (s, 2 H), 4.22 (d, 1 H, J )
9.3 Hz), 3.94 (t, 1 H, J ) 8.7 Hz), 3.68-3.82 (m, 4 H), 3.50-3.68
(m, 1 H), 3.01 (q, 6 H, J ) 7.2 Hz), 1.24 (t, 9 H, J ) 7.2 Hz); 13
C
NMR (75 MHz, CDCl3) δ 138.6, 138.4, 138.2, 138.1, 128.9, 128.4,
128.1, 127.9, 127.8, 127.7, 127.7, 127.5, 127.4, 88.2, 86.7, 80.5,
78.6, 77.5, 75.8, 75.1, 75.0, 73.3, 69.1, 46.0, 8.5; NI-FAB-MS m/z
604 M-.
Triethylammonium (2S,3R,4S,5R,6R)-3,4,5-Triacetoxy-6-(ac-
etoxymethyl)tetrahydro-2H-pyran-2-sulfonate (34). Dimethyl-
dioxirane (5 mL of a 0.079 M solution in acetone) was added to a
flask containing a solution of 46 mg (0.113 mmol) of thioacetate
3046 in 1 mL of acetone at 0 °C. The solution was stirred at 0 °C
(43) Zanini, D.; Park, W. K. C.; Roy, R. Tetrahedron Lett. 1995, 36,
7383-7386.
(44) Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 2659-2666.
(45) Scheffler, G.; Behrendt, M. E.; Schmidt, R. R. Eur. J. Org. Chem.
2000, 3527-3539.
(46) Blanc-Muesser, M.; Defaye, J.; Driguez, H. J. Chem. Soc., Perkin
Trans. 1 1982, 15-18.
J. Org. Chem, Vol. 71, No. 4, 2006 1387

Knapp et al.
for 16 h, concentrated, and then chromatographed on silica with
98:1:1 dichloromethane/methanol/triethylamine as the eluant to give
50 mg (86%) of sulfonate 34, Rf 0.2 (98:1:1 dichloromethane/
methanol/triethylamine): 1H NMR (300 MHz, CDCl3) δ 6.12 (dd,
1 H, J ) 9.3, 9.9 Hz), 4.86-5.14 (m, 3 H), 4.73 (ddd, 1 H, J )
10.2, 3.6, 2.4 Hz), 4.26 (dd, 1 H, J ) 12.9, 3.9 Hz), 4.12 (dd, 1 H,
J ) 12.9, 2.4 Hz), 2.92 (q, 6 H, J ) 7.5 Hz), 2.07, 2.05, 2.00, 1.98
(4 s, 3 H each), 1.24, (t, 9 H, J ) 7.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 171.0, 170.7, 170.2, 169.8, 82.9, 70.9, 70.3, 70.3, 68.7,
62.3, 46.4, 21.4, 21.2, 21.2, 20.0, 10.0; NI-FAB-MS m/z 411 M-.
Attempted Synthesis of Anomeric Sulfonyl Chlorides (Table
2). A solution of 43 mg (0.164 mmol) of triphenylphosphine in
500 µL of dichloromethane was stirred at -20 °C bath temperature.
Sulfuryl chloride (15 µL, 0.180 mmol) was added dropwise,
followed by slow addition of a solution of 42 mg (0.082 mmol) of
32 in 500 µL of dichloromethane, with the temperature maintained
at -20 °C. The reaction was allowed to warm to 23 °C and was
stirred at that temperature for 2 h. The solution was concentrated
and then chromatographed on silica with 1:3 ethyl acetate/hexanes
as the eluant to give 21 mg (70%) of tetra-O-acetyl-R-D-glucopy-
ranosyl chloride 35 as an off-white solid, mp 70-72 °C, Rf 0.25
maintained at -40 °C. After 0.5 h, 48 µL (0.465 mmol) of
diethylamine was added, followed by 186 µL (1.08 mmol) of
diisopropylethylamine. The dry ice bath was removed and the
reaction was allowed to come to 23 °C and to stir for 2 h. The
solution was concentrated and then chromatographed on silica gel
with 1:4 ethyl acetate/dichloromethane as the eluant to give 90 mg
(58%) of sulfenamide 44 as a colorless oil, Rf 0.6 (7:3 ethyl acetate/
dichloromethane), with 1H NMR spectrum and TLC behavior
identical to that described above.
N-[(2R,3R,4R,5S,6R)-2-(Diethylaminothio)-4,5-dihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide (45). Sulfe-
namide triacetate 44 (57 mg, 0.131 mmol) was dissolved in 2 mL
of methanol at 0 °C bath temperature. Sodium methoxide (13 µL
of a 1 M solution in methanol) was added at 0 °C. The reaction
was stirred for 2 h, concentrated, and then chromatographed on
silica gel with 1:19 methanol/dichloromethane as the eluant to give
38 mg (95%) of triol 45 as a white solid, mp 185 °C, Rf 0.4 (1:9
methanol/dichloromethane): 1H NMR (300 MHz, D2O) δ 5.58 (d,
1 H, J ) 5.6 Hz), 3.92-4.00 (m, 2 H), 3.82 (dd, 1 H, J ) 12.0, 2.8
Hz), 3.75 (dd, 1 H, J ) 12.0, 4.8 Hz), 3.28-3.40 (m, 2 H), 2.80-
2.99 (m, 4 H), 2.00 (s, 3 H), 1.14 (t, 6 H, J ) 7.2 Hz); 13C NMR
(100 MHz, D2O) δ 173.6, 87.5, 75.5, 73.0, 72.7, 62.7, 55.8, 53.4,
22.7, 14.2; FAB-MS m/z 331 MNa+.
1
(1:3 ethyl acetate/hexanes). The mp and H NMR spectrum of 35
matched the literature data.47
(2R,3S,4R,5R,6S)-5-Acetamido-2-(acetoxymethyl)-6-(diethyl-
aminothio)tetrahydro-2H-pyran-3,4-diyl Diacetate (47). A 25 mL
flask containing a solution of 94.3 mg (0.233 mmol) of thioacetate
27 in 2 mL of dichloromethane was cooled to -78 °C bath
temperature. Bromine (256 µL, 0.256 mmol) was added, and the
reaction mixture was maintained at -78 °C. After 0.5 h, 29 µL
(0.279 mmol) of diethylamine was added, followed by 122 µL
(0.699 mmol) of diisopropylethylamine. At this point, the dry ice
bath was removed and the reaction was allowed to stir for 2 h. The
solution was concentrated and then chromatographed on silica gel
with 1:4 ethyl acetate/dichloromethane as the eluant to give 84.5
mg (65%) of sulfenamide 47 as a colorless oil, Rf 0.6 (7:3 ethyl
acetate/dichloromethane): 1H NMR (400 MHz, CDCl3) δ 5.43 (d,
1 H, J ) 8.7 Hz), 5.22 (t, 1 H, J ) 9.3 Hz), 5.04 (t, 1 H, J ) 9.09
Hz), 4.68 (d, 1 H, J ) 10.8 Hz), 4.11-4.26 (m, 2 H), 3.95 (q, 1 H,
J ) 10.2 Hz), 3.67 (ddd, 1 H, J ) 9.9, 5.4, 2.4 Hz), 2.84-3.02 (m,
4 H) 2.07, 2.04, 2.03, 1.96 (4 s, 3 H each), 1.13 (t, 6 H, J ) 6.9
Hz); 13C NMR (100 MHz, CDCl3) δ 171.5, 170.7, 169.7, 169.3,
87.1, 71.5, 69.3, 68.2, 62.3, 52.2, 52.0, 23.2, 20.7, 20.6, 13.7; FAB-
MS m/z 457 MNa+. An earlier literature description of 47 records
Treatment of 32 with phosphorus pentachloride or oxalyl chloride
in the same fashion gave tetra-O-acetyl-R-D-glucopyranosyl chloride
1
35 as the only carbohydrate product identifiable by TLC and H
NMR analysis.
Similar treatment of sulfonate 33 with 1.75 equiv of phosphoryl
chloride gave 2,3,4,6-tetra-O-benzyl-R-D-glucopyranosyl chloride
1
36 as the only identifiable carbohydrate product. The H NMR
spectrum matched the literature values.48
2,3,4,6-Tetra-O-benzyl-R/â-D-glucopyranosyl Fluoride (37).
(Diethylamino)sulfur trifluoride (15 µL, 0.115 mmol) was added
to a solution of 75.8 mg (0.108 mmol) of 33 in 2 mL of
dichloromethane at 0 °C. The reaction was allowed to stir at 23 °C
for 2 h, by which time TLC analysis indicated the consumption of
starting material. 1H NMR analysis of the crude concentrated
reaction product and comparison with the literature spectra49 showed
two carbohydrate products, the anomeric fluorides 35, as a 1:1
mixture.
(2R,3S,4R,5R,6R)-5-Acetamido-2-(acetoxymethyl)-6-(N,N-di-
ethylaminothio)tetrahydro-2H-pyran-3,4-diyl Diacetate (44). A
solution of 108.8 mg (0.299 mmol) of mercaptan 21 in 2 mL of
dichloromethane was stirred at -78 °C bath temperature. Bromine
(330 µL, 0.300 mmol) was added, and the reaction was maintained
at -78 °C. After 0.5 h, 31 µL (0.300 mmol) of diethylamine was
added, followed by 156 µL (8.98 mmol) of diisopropylethylamine.
At this point, the dry ice bath was removed and the reaction was
allowed to stir for 2 h. The solution was concentrated and then
chromatographed on silica gel with 1:4 ethyl acetate/dichlo-
romethane as the eluant to give 84.5 mg (65%) of 44 as a colorless
oil, Rf 0.6 (7:3 ethyl acetate/dichloromethane): 1H NMR (400 MHz,
CDCl3) δ 5.76 (d, 1 H, J ) 8.8 Hz), 5.50 (d, 1 H, J ) 5.6 Hz),
5.01 (t, 1 H, J ) 9.6 Hz), 4.81 (dd, 1 H, J ) 11.2, 9.6 Hz), 4.48
(ddd, 1 H, J ) 11.2, 8.8, 5.6 Hz), 3.38 (ddd, 1 H, J ) 10.0, 4.8,
2.4 Hz), 4.26 (dd, 1 H, J ) 12.0, 4.8 Hz), 4.10 (dd, 1 H, J ) 12.0,
2.4 Hz), 2.81-2.99 (m, 4 H) 2.08, 2.03, 2.02, 1.97 (4 s, 3 H each),
1.14 (t, 6 H, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 171.5,
170.7, 169.7, 169.3, 87.1, 71.5, 69.3, 68.2, 62.3, 52.2, 52.0, 23.2,
20.7, 20.6, 13.7; FAB-MS m/z 457 MNa+.
1
a different H NMR (CDCl3) spectrum.37b
N-((2S,3R,4R,5S,6R)-2-(Diethylaminothio)-4,5-dihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (48). A
solution of 30 mg (0.069 mmol) of 47 in 1 mL of methanol at 0 °C
bath temperature was treated with 6 µL of a 1 M solution of
methanol sodium methoxide. After 2 h at 0 °C, the reaction mixture
was concentrated and then chromatographed on silica gel with 1:19
methanol/dichloromethane as the eluant to give 38 mg (95%) of
48 as a colorless oil, Rf 0.4 (1:9 methanol/dichloromethane): 1H
NMR (300 MHz, D2O) δ 4.58 (d, 1 H, J ) 10.2 Hz), 3.87 (dd, 1
H, J ) 12.0, 2.4 Hz), 3.79 (t, 1 H, J ) 9.9 Hz), 3.70 (dd, 1 H, J
) 12.0, 5.4 Hz), 3.47 (dd, 1 H, J ) 9.6, 8.7 Hz), 3.26-3.42 (m, 2
H), 2.90 (q, 4 H, J ) 7.2 Hz), 1.95 (s, 3 H), 1.16 (t, 6 H, J ) 7.2
Hz); 13C NMR (75 MHz, D2O) δ 173.3, 91.3, 82.7, 77.4, 71.9,
62.9, 56.8, 52.6, 23.1, 14.0; FAB-MS m/z 331 MNa+.
(2R,3S,4R,5R,6R)-5-Acetamido-2-(acetoxymethyl)-6-[(S)-N,N-
diethylsulfinamoyl]tetrahydro-2H-pyran-3,4-diyl Diacetate (49).
m-CPBA (40 mg, 0.232 mmol) was added to a mixture of 41.7 mg
(0.096 mmol) of 44, 24.2 mg (0.288 mmol) of sodium hydrogen-
carbonate, and 2 mL of 1,2-dichloroethane at 23 °C. The reaction
was stirred for 12 h at 23 °C. Dichloromethane (2 mL) was added,
and the resulting mixture was washed three times with aqueous
sodium bicarbonate. Concentration of the organic layer and then
chromatography on silica with 7:3 ethyl acetate/dichloromethane
as the eluant gave 37 mg (86%) of 49 as a colorless oil, Rf 0.2 (7:3
ethyl acetate/dichloromethane): 1H NMR (300 MHz, CDCl3) δ 7.04
The preparation of 44 from 21 using sulfuryl chloride was also
successful. A solution of 129.3 mg (0.356 mmol) of 21 in 5 mL of
dichloromethane was stirred at -40 °C (bath temperature). Sulfuryl
chloride (33 µL, 0.414 mmol) was added, and the reaction was
(47) Jansson, K.; Noori, G.; Magnusson, G. J. Org. Chem. 1990, 55,
3181-3185.
(48) Cicchillo, R. M.; Norris, P. Carbohydr. Res. 2000, 328, 431-434.
(49) Drew, K. N.; Gross, P. H. J. Org. Chem. 1991, 56, 509-513.
1388 J. Org. Chem., Vol. 71, No. 4, 2006

New Glycomimetics
(d, 1 H, J ) 9.6 Hz), 5.41 (dd, 1 H, J ) 11.1, 9.3 Hz), 5.2 (t, 1 H,
J ) 9.6 Hz), 4.82 (ddd, 1 H, J ) 11.1, 9.6, 5.1 Hz), 4.49 (d, 1 H,
J ) 5.1 Hz), 4.16 (dd, 1 H, J ) 12.6, 4.8 Hz), 4.00-4.12 (m, 2
H), 3.33 (quintet, 2 H, J ) 7.5 Hz), 3.21 (quintet, 2 H, J ) 7.5
Hz), 2.08, 2.04, 2.03, 1.96 (4 s, 3 H each), 1.24 (t, 6 H, J ) 7.5
Hz); 13C NMR (75 MHz, CDCl3) δ 170.5, 170.3, 170.1, 169.0,
87.4, 73.3, 71.5, 68.5, 62.1, 50.3, 41.8, 23.4, 20.8, 20.7, 20.7, 14.7;
FAB-MS m/z 473 MNa+.
(2R,3S,4R,5R,6R)-5-Acetamido-2-(acetoxymethyl)-6-(N,N-di-
ethylsulfamoyl)tetrahydro-2H-pyran-3,4-diyl Diacetate (50). m-
CPBA (15 mg, 0.058 mmol) was added to a mixture of 13 mg
(0.029 mmol) of 49, 7.3 mg (0.087 mmol) of sodium bicarbonate,
and 1 mL of 1,2-dichloroethane at 23 °C. The reaction was heated
for 1 h at 40 °C and then cooled and diluted with 1.5 mL of
dichloromethane. The organic solution was washed three times with
aqueous sodium bicarbonate and then concentrated and chromato-
graphed on silica with 1:4 ethyl acetate/dichloromethane as the
eluant to give 13.4 mg (100%) of 50 as a colorless oil, Rf 0.6 (7:3
ethyl acetate/dichloromethane): 1H NMR (300 MHz, CDCl3) δ 6.18
(d, 1 H, J ) 9.0 Hz), 5.63 (dd, 1 H, J ) 11.4, 9.3 Hz), 5.16 (dd,
1 H, J ) 10.2, 9.6 Hz), 4.91 (d, 1 H, J ) 6.3 Hz), 4.52-4.70 (m,
2 H), 4.17 (dd, 1 H, J ) 12.6, 4.2 Hz), 4.09 (dd, 1 H, J ) 12.6, 2.4
Hz), 3.42 (quintet, 2 H, J ) 7.5 Hz), 3.28 (quintet, 2 H, J ) 7.5
Hz), 2.09, 2.04, 2.04, 2.00 (4 s, 3 H each), 1.22 (t, 1 H, J ) 7.5
Hz); 13C NMR (75 MHz, CDCl3) δ 170.9, 170.7, 170.3, 169.1,
85.6, 72.4, 69.7, 67.7, 62.0, 50.3, 41.8, 23.3, 20.8, 20.7, 14.5; FAB-
MS m/z 489 MNa+.
N-((2R,3R,4R,5S,6R)-2-(N,N-Diethylsulfamoyl)-4,5-dihydroxy-
6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (51). Sul-
fonamide 50 (15 mg, 0.032 mmol) was dissolved in 1 mL of
methanol at 0 °C bath temperature. Sodium methoxide (3 µL of a
1 M solution in methanol) was added at 0 °C. The reaction mixture
was stirred for 2 h at 23 °C, concentrated, and then chromatographed
on silica with 1:19 methanol/dichloromethane as the eluant to give
11 mg (100%) of 51 as a colorless oil, Rf 0.4 (1:9 methanol/
dichloromethane): 1H NMR (300 MHz, D2O) δ 5.12 (d, 1 H, J )
5.4 Hz), 4.02-4.14 (m, 3 H), 3.82 (dd, 1 H, J ) 12.3, 2.4 Hz),
3.00 (dd, 1 H, J ) 12.3, 4.8 Hz), 3.22-3.52 (m, 5 H), 1.99 (s, 3
H), 1.20 (t, 6 H, J ) 7.2 Hz); 13C NMR (75 MHz, D2O) δ 174.4,
87.2, 78.8, 71.8, 71.1, 62.6, 54.0, 43.4, 22.8, 15.4; FAB-MS m/z
363 MNa+.
Acknowledgment. We are grateful to Merck & Co., Syn-
Chem Research, and NIH for financial support, to UNCF-Merck
for a graduate fellowship to E.D., to Rutgers University for a
Reid graduate fellowship to B.A., and to Mr. Mohannad Abdo
for experimental assistance.
Supporting Information Available: 1H and 13C NMR spectra
for new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0520386
J. Org. Chem, Vol. 71, No. 4, 2006 1389