Highly diastereoselective oxidation of 2-amino-2-deoxy-1-thio-β-D-glucopyranosides: Synthesis of imino sulfinylglycosides

Article abstract of DOI:10.1021/jo026519q

A synthetic route to imino thioglycosides and to imino sulfinylglycosides has been developed. A detailed study on the diastereoselective oxidation of 2-amino-2-deoxy-1-thio-β-D-glucopyranosides is reported. It has been shown that the stereochemical outcome of the oxidation is highly dependent on the protective group of the amine function. While the oxidation of iminothioglycosides is slightly diastereoselective (up to 30% de in favor of the R_S sulfoxide), a single isomer is obtained in the case of tetrachlorophthalimido derivatives. The absolute configuration of the sulfinyl glycoside was ascertained by NMR analysis using our recent model on the basis of the exo-anomeric effect corroborated by X-ray crystallography.

Full text of DOI:10.1021/jo026519q

High ly Dia ster eoselective Oxid a tion of
2-Am in o-2-d eoxy-1-th io-â-D-glu cop yr a n osid es: Syn th esis of Im in o
Su lfin ylglycosid es
Noureddine Khiar,*,† Inmaculada Ferna´ndez,‡ Cristina S. Arau´jo,†,‡ J ose´-Antonio Rodr´ıguez,†
Bele´n Sua´rez,† and Eleuterio AÄ lvarez†
Instituto de Investigaciones Quı´micas, C.S.I.C.-Universidad de Sevilla, c/ . Ame´rico Vespucio, s/ n.,
Isla de la Cartuja, 41092 Sevilla, Spain, and the Departamento de Qu´ımica Orga´nica y Farmace´utica,
Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain
khiar@cica.es
Received October 3, 2002
A synthetic route to imino thioglycosides and to imino sulfinylglycosides has been developed. A
detailed study on the diastereoselective oxidation of 2-amino-2-deoxy-1-thio-â-D-glucopyranosides
is reported. It has been shown that the stereochemical outcome of the oxidation is highly dependent
on the protective group of the amine function. While the oxidation of iminothioglycosides is slightly
diastereoselective (up to 30% de in favor of the RS sulfoxide), a single isomer is obtained in the
case of tetrachlorophthalimido derivatives. The absolute configuration of the sulfinyl glycoside was
ascertained by NMR analysis using our recent model on the basis of the exo-anomeric effect
corroborated by X-ray crystallography.
In tr od u ction
As a part of our recent interest in the synthesis and
utilization of chiral sulfoxides in catalytic asymmetric
synthesis promoted by transition metals,1 we became
interested in the synthesis of bidentated S/N ligands
derived from sugars such as I and II (Figure 1). These
compounds are thought to chelate the transition metal
through the nitrogen and the sulfur atoms in I and
through the nitrogen and either the sulfur or the oxygen
atoms in the case of II.2 An inherent characteristic of
thioether ligands such as I is that upon coordination to
the metal the sulfur atom becomes stereogenic. While the
close proximity of the stereogenic center to the coordina-
tion sphere of the transition metal may be beneficial,3
the low inversion barrier of the sulfur metal bond may
lead to an erosion of the enantioselectivity of the catalytic
process.4 Keeping this in mind, the synthesis of diaste-
reomerically pure sulfinyl glycosides II was designed as
a stereochemically well-defined S/N ligands. To under-
F IGURE 1.
take the investigation of I and II ligand capacities, two
basic problems must be solved. The first one is a modular
and general method for the synthesis of conveniently
functionalyzed 2-amino-2-deoxy-â-thioglycosides, and the
second problem is an easy method for the determination
of the absolute configuration of the sulfinyl glycosides.
In this paper, we report on a practical synthesis of
tetrachlorophthalimide-protected phenyl and ethyl 2-ami-
no-2-deoxy-1-thio-â-D-glucopyranosides III en route to
compounds I and II. While the oxidation of iminothiogly-
cosides I is slightly diastereoselective, the oxidation of
III has resulted in an unusual highly diastereoselective
process. Applying our empirical NMR rule for the deter-
mination of the absolute configuration of anomeric sulf-
oxides,5 corroborated by X-ray analysis, we present a
rationalization of the diastereoselectivity observed and
extend it to other â-thioglycosides.6 It is worth mention-
ing that the obtained sulfinyl glycosides, as well as the
parent thioglycosides, are of interest for the synthesis of
oligosaccharides containing â-linked hexosamines, com-
ponents of many natural and biologically active carbo-
hydrates.7 Recently, Kahne’s route using anomeric sulf-
oxides for the synthesis of glycosides has emerged as one
† Instituto de Investigaciones Qu´ımicas, C.S.I.C-Universidad de
Sevilla.
‡ Facultad de Farmacia, Universidad de Sevilla.
(1) (a) Khiar, N.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett. 1993,
34, 123. (b) Khiar, N.; Alcudia, F.; Espartero, J .-L.; Rodr´ıguez, L.;
Fernandez, I. J . Am. Chem. Soc. 2000, 122, 7598. (c) Khiar, N.; Arau´jo,
C. S.; Alcudia, F.; Ferna´ndez, I. J . Org. Chem. 2002, 67, 345.
(2) For some use of S,N ligands in metal-catalyzed asymmetric
synthesis see: (a) Allen J . V.; Bower, J . F.; Williams, J . M. J .
Tetrahedon: Asymmetry 1994, 5, 1895. (b) Hiroi, K.; Watanabe, K.; Abe,
I.; Koseki, M. Tetrahedron Lett.2001, 42, 7617. (c) Boog-Wick, K.;
Pregosin, P. S.; Trabesinger, G. Organometallics 1998, 17, 3254.
(3) Evans, D. A.; Campos, K. R.; Tedrow, J . S.; Michael, F. E.; Gagne´,
M. R. J . Am. Chem. Soc. 2000, 122, 7905.
(4) (a) Abel, E.; Bhargava, S. K.; Orrell, K. G. Prog. Inorg. Chem.
1984, 32, 1-118. (b) Abel, E.; Dormer, J .; Ellis, D.; Orrell, K. G.; Sik,
V.; Hursthouse, M. B.; Mazid, M. A. J . Chem. Soc., Dalton Trans. 1992,
1073-1080.
(5) Khiar, N. Tetrahedron Lett. 2000, 41, 9059.
(6) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. L.; Wink,
D. J . J . Am. Chem. Soc. 2002, 124, 6028.
10.1021/jo026519q CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/25/2003
J . Org. Chem. 2003, 68, 1433-1442
1433

Khiar et al.
SCHEME 1a
of the most promising approaches for the ever seeked
“general glycosidation reaction”.8 The sulfoxide method,
which has been developed originally for the glycosidation
of hindered alcohols, has been recently used inter alia
for the one-pot sequential formation of various glycosidic
bonds,9 for the synthesis of carbohydrates, including
carbohydrate libraries on solid support,10 and finally, for
the synthesis of â-mannosides.11 While the stereochemical
outcome of the reaction is independent of the stereo-
chemistry of the sulfinyl sulfur and at the anomeric
carbon, we12 and others13 have reported that RS and SS
sulfinyl glycosides are hydrolyzed with different kinetics
by triflic acids and react in a complete diastereoselective
manner with glycosidases.14 Additionally, it has recently
been shown that in some cases a diastereomeric sulfoxide
is an active glycosylating agent while the other is not.15
On the other hand, the use of thioglycosides as glycosi-
dase-resistant analogues of glycoside is well docu-
mented.16 Therefore, the corresponding sulfinyl analogues
are expected not only to alter the lipophilicity but also
to vary the geometrical disposition of the sugar moiety
about the aglycon.17 Such analogues, which should mark-
edly affect the biological activity, make sulfinyl glycosides
interesting on their own and the knowledge of their
stereochemistry of sum interest.
a
One step synthesis of ethyl and phenyl thioglycosides 2 and
3.
F IGURE 2. Possible transformations of thioglycoside type III.
starting material. Nevertheless, Olson et al. have recently
reported on the inertness of the easily accessible axial
acetate 121 toward thioglycosidation, despite the use of
different reagent systems, such as ethanethiol or trime-
thyl(ethylthio)silane in the presence of various Lewis
acids.
As 1,2-trans-acetates are known to react faster than
their 1,2-cis counterparts, a three-step process, isomer-
izing the R-acetate to the â-acetate, was developed,
leading to the desired ethyl thioglycoside 2, in 35%
overall yield. We have actually found that the use of the
standard conditions, ethanethiol (2 equiv) with boron
trifluoride diethyl ether (4 equiv) at reflux, gives in 2 h
cleanly the desired compound in nearly quantitative yield
(Scheme 1).
Using the same conditions, phenyl thioglycoside 3 has
also been obtained in excellent yield (Scheme 1). This
finding makes this route very attractive for large-scale
synthesis access to TCP-protected 2-amino-2-deoxythiogly-
cosides, in good overall yields from glucosamine hydro-
chloride.
The usefulness of this synthon is illustrated in Figure
2, where all the possible transformations of 2 affording
useful intermediates for the synthesis of oligosaccharides
containing â-linked hexosamines are presented. Treat-
ment with NBS and water in acetone can give the
corresponding lactol22,23 en route to the trichloroacetimi-
date derivative,20 while the treatment with NBS and
DAST will lead to the axial fluroride.24
Resu lts a n d Discu ssion
The widely used method for the synthesis of thiogly-
cosides is the Lewis-acid-catalyzed substitution of the
anomeric acetate with the desired thiol.18 A large number
of catalysts have been used in this transformation,
including zinc chloride, titanium tetrachloride, ferric
chloride, boron trifluoride diethyl etherate, and zirconium
chloride. Additionally, to obtain the desired 1,2-trans-
iminothioglycoside in a diastereoselective manner, a
glycosyl donor with an easily removable participating
group at the 2-position is needed. Tetrachlorophthalim-
ide-protected amino derivative 1, introduced simulta-
neously by Fraser-Reid19 and Schmidt,20 which symbol-
izes the aforementioned requirement has been chosen as
(7) (a) Banoub, J .; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92,
1167. (b) Debenham, J .; Rodebaugh, R.; Fraser-Reid, B. Liebigs Ann./
Recueil 1997, 791.
(8) (a) Kahne, D.; Walker, S.; Cheng, Y.; Engen D. V. J . Am. Chem.
Soc. 1989, 111, 6881. (b) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997,
119, 11217. (c) Gildersleeve, J .; Pascal, R. A. J r.; Kahne, D. J . Am.
Chem. Soc. 1998, 120, 5961.
(9) Raghaven, S.; Kahne, D. J . Am. Chem. Soc. 1993, 115, 1580.
(10) Liang, R.; Yan, L.; Loebach, J .; Ge, M.; Uozumi, Y.; Sekanina,
K.; Horan, N.; Gildersleeve, J .; Thompson, C.; Smith, A.; Biswas, K.,
Still, W. C.; Kahne, D. Science 1996, 274, 1520.
(11) Crich, D. Sun, S. J . Org. Chem. 1997, 62, 1198.
(12) Khiar, N.; Alonso, I.; Rodriguez, N.; Fernandez-Mayoralas, A.;
J imenez-Barbero, J ., Nieto, O., Cano, F.; Foces-Foces, C.; Martin-
Lomas, M. Tetrahedron Lett. 1997, 38, 8267.
(13) Karthaus, O.; Shoda, S.; Kobayashi, S. Tetrahedron: Asymmetry
1994, 5, 2213.
(14) It is interesting to note that the diastereoselective hydrolysis
of SS sulfinyl glycosides reported in refs 12 and 13 can be well
understood using Vasella’s recent lateral protonation model for gly-
cosidase enzymes; see: Heightman, T. D. Vasella, A. T. Angew. Chem.,
Int. Ed. 1999, 38, 750.
(15) Ferrie`res, V.; J outel, J .; Boulch, R.; Roussel, M.; Toupet, L.;
Plusquellec, D. Tetrahedron Lett. 2000, 41, 5515.
(16) Driguez, H. Top. Curr. Chem. 1997, 187, 85.
(17) Showalter, H. D. H.; Winters, R. T.; Sercel, A. D.; Michel, A.
Tetrahedron Lett. 1991, 32, 2849.
(19) Debenham, J . S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J .
Am. Chem. Soc. 1995, 117, 3302.
(20) Castro-Palomino, J . C.; Schmidt, R. R. Tetrahedron Lett. 1995,
36, 5343.
(21) Olsson, L.; Kelberlau, S.; J ia, Z. J .; Fraser-Reid, B. Carbohydr.
Res. 1998, 314, 273.
(22) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Shulze, T.
J .; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabushi, Y.; Smith, A. L.;
Nicolaou, K. C. J . Am. Chem. Soc. 1993, 115, 7593.
(23) Motawia, M. S.; Marcussen J .; Moeller, B. L. J . Carbohydr.
Chem. 1995, 14, 1279.
(18) (a) Ferrier, R. J .; Furneaux, R. H. Carbohydr. Res. 1976, 52,
63. (b) Garegg, P. J . Adv. Carbohydr. Chem. Biochem. 1997, 52, 179
and references therein.
(24) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P. J . Am Chem.
Soc. 1984, 106, 4189.
1434 J . Org. Chem., Vol. 68, No. 4, 2003

Oxidation of 2-Amino-2-deoxy-1-thio-â-D-glucopyranosides
SCHEME 2a
SCHEME 4a
a
a
Key: (a) PivCl, py, DMAP, reflux (56%); (b) NH2(CH2)2NH2,
Key: (a) HCl, H2O/acetone, 70 °C, quant; (b) BzCl, py, DMAP
CH3CN/EtOH/THF, 70 °C (41%); (c) p-MeOC6H4CHO, CuSO4,
CH2Cl2 (64%).
(66%); (c) NH2(CH2)2NH2, CH3CN/EtOH/THF, 70 °C (43%); (d)
p-MeOC6H4CHO, CuSO4, CH2Cl2 (61%).
SCHEME 5a
SCHEME 3a
a
a
Key: (a) Pd(CH3CN)2Cl2, CH2Cl2 (80%); (b) m-CPBA, -78 °C,
Key: (a) Pd(CH3CN)2Cl2, CH2Cl2 (80%); (b) m-CPBA, -78 °C,
CH2Cl2 (80%).
CH2Cl2 (90%).
To get the desired S/N ligands, it was necessary the
deprotection of the amine group. Owing to the presence
of acetates on the C-3, C-4, and C-5 positions, the
aminolysis of the TCP group could not be made directly,
because of the concomitant migration of the acetyl group
to the amine function.
gluco, galacto and mano series always give the sulfoxides
with S absolute configuration majoritarly.6 Our actual
results, as well as those recently reported by Ferrieres
and Plusquellec,27 indicate that the oxidation of â-thiogly-
cosides depends not only on the configuration of C-2, but
also on the nature of the protective group. To get better
insight in the stereochemical outcome of the oxidation,
iminothioglycosides with a bulky pivaloyl protective
group were planned and synthesized as before.
To resolve this problem the acetate groups were
changed to benzoate esters. Acid hydrolysis of 2 leads to
the triol 4,24 which upon treatment with 5 molar equiv
of benzoyl chloride in pyridine afforded the tribenzoylated
compound 5 in good yield. Treatment of the fully pro-
tected compound 5 with ethylenediamine at 60 °C, as
described by Fraser-Reid, leads to the free amine 6 in
modest yield (Scheme 2).25 Imination of compound 6 with
p-methoxybenzaldehyde using molecular sieves as dehy-
drating agent afforded the desired iminothioglycoside 7
in very low yield (<20%). Gratifyingly, using CuSO4 as
recently described by Ellman’s group afforded the desired
imine in acceptable yield.26 Reacting the iminothiogly-
coside 7 with PdCl2(CH3CN)2, in methylene chloride at
room temperature, afforded the corresponding palladium-
Pivaloylation of the triol 4, using 6 equiv. of pivaloyl
chloride in pyridine at 80 °C afforded 10, aminolysis as
before led to the amino thioglycoside 11 and imination
with p-methoxybenzaldehyde using CuSO4 as dehydrat-
ing agent afforded the desired imino thioglycoside 12 in
acceptable yield (Scheme 4). Reacting the iminothiogly-
coside 12 with PdCl2(CH3CN)2, as before, afforded the
corresponding palladium(II) complexes 13 in good yield
(Scheme 5). NMR analysis of the crude mixture showed
the formation of a 1:1 diastereomeric mixture. On the
other hand, the oxidation of 12 as usual, using m-CPBA
at -78 °C, afforded a 55:45 mixture of anomeric sulfoxide
14, paralleling again the Pd(II) complex formation (Scheme
5). Here again, the slightly major isomer was shown to
have the RS absolute configuration at the sulfinyl sulfur.
Deter m in a tion of th e Absolu te Con figu r a tion of
Su lfin yl Glycosid es. The stereochemical outcome of the
diastereoselective oxidation of thioglycoside has received
much interest recently. From our study on â-thioglyco-
sides,5,12 we have shown that the oxidation is highly
dependent on the substituent at C-2 of the sugar. A high
diastereoselection is observed in the case of sugars with
a free C2-OH, while a slightly diastereoselective process
results in the case of fully protected sugars. In the case
of R-thioglycosides, Crich has recently shown that the
1
(II) complexes 8 in excellent yield (Scheme 3). H NMR
analysis shows that the reaction product is a mixture of
two diastereomeric compounds in a 65:35 ratio. This
result indicates that the use of iminothioglycoside-type
7 in palladium-catalyzed asymmetric synthesis may be
compromised by the formation of diastereomeric com-
plexes having opposite configuration at the sulfur atom.
Diastereomerically pure imino sulfoxides embody a
configurationally stable S/N ligand, able to give a single
palladium complex. Unfortunately, oxidation of imi-
nothioglycoside 7 with m-CPBA, in methylene chloride
as usual, leads to the corresponding sulfoxides 9 in a 65:
35 mixture. Surprisingly, the major isomer was shown
unambiguously (vide infra) to have the R absolute
configuration at the sulfinyl sulfur. It has recently been
assumed that the oxidation of â-thioglycosides in the
oxidation is highly diastereoselective leading to RS
sulfi-
nyl glycosides mostly as single isomer.28 The accumulated
results have prompted the quick conclusion that in the
(25) Debenham, J . S.; Debenham, S. D.; Fraser-Reid, B. Bioorg. Med.
Chem. 1996, 4, 1909.
(26) Liu, G., Cogan, D. A.; Owens, T. D.; Tang, T. P., Ellman, J . A.
J . Org. Chem. 1999, 64, 1278.
(27) Misbahi, K.; Lardic, M.; Ferrie`re, V.; Noiret, N.; Kerbal, A.;
Plusquellec, D. Tetrahedron: Asymmetry 2001, 12, 2389.
(28) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. L.;
Wink, D. J . Chem. Commun. 1998, 2763.
J . Org. Chem, Vol. 68, No. 4, 2003 1435

Khiar et al.
SCHEME 6
the SS epimer,34 supporting the existence of an hyper-
conjugative delocalization of the lone pair of the sulfinyl
sulfur to σ* orbital of the C1-O5 (Figure 3).35 In this
regard, it is worth mentioning that Buist has recently
determined the conformational behavior of the two ethyl
sulfinyl glycosides epimers by semiempirical (AM1/
MOPAC) calculation.30b While two low energy conformers
were found for the SS sulfinyl glycoside, a single confor-
mation was detected for the RS counterpart. Interestingly,
the later conformation was that with the lone pair of the
sulfinyl sulfur anti to O-5, and the ethyl substituent anti
to C-2, that is the exo-anomeric conformation.
F IGURE 3. Newman projection of â-ethylthioglycosides,
â-(RS)-sulfinyl glycosides, and â-(SS)-sulfinyl glycosides.
case of pyranosides with 1,2-trans-diequatorial substit-
uents, the sense (SS) and the degree of diastereoselec-
tivity (modest) are a general feature.6 To ascertain the
diastereoselectivity observed during this work, it was
necessary to determine the absolute configuration at the
sulfinyl sulfur of the obtained sulfinyl glycosides. The
widely used approach for the determination of the
absolute configuration of chiral sulfoxides has been the
utilization of NMR spectroscopy using chiral shift re-
agents such as 9-anthryl-1,1,1-trifluoroethanol,29 R-meth-
oxyyphenylacetic acid,30 and R-(-)-N-(3,5-dinitrobenzoyl)-
R-phenylethylamine.31 The success of using chiral shift
reagents as tool for the elucidation of the stereochemistry
of the sulfoxide depends on the stability of the complex
formed by hydrogen bonds between their acidic OH
groups and the basic sulfinic oxygen. Nevertheless, the
instability of the complexes implies that the chemical
shift differences between the diastereomeric complexes
are usually very small or, in some cases, nonsystematic.
After analyzing the physical data of a large number of
sulfinyl glycosides, we have recently reported a simple
method for the determination of the absolute configura-
tions of sulfinyl glycosides.5 This method is based on a
simple analysis of 1H or 13C NMR data, thanks to a
general characteristic conformational behavior of the two
anomeric sulfoxides epimers. We have observed that in
the case of ethyl (and most likely other alkyl) sulfox-
ides6,32 the nonequivalence of the diastereotopic protons
Hpro- and Hpro- , vicinal to the sulfoxide group, is larger
Accordingly, the chemical shift of the anomeric carbon
of the major isomer of benzoylated sulfoxide 9 is 88.3 ppm
and the nonequivalence of the diastereotopic protons
Hpro- and Hpro- is 108.6 Hz. Whereas the anomeric carbon
R
S
of the minor is more deshielded (91.1 ppm), and the
splitting of the diastereotopic protons Hpro- and Hpro- is
R
S
smaller (42.1 Hz). These data indicate that the major
isomer has an RS absolute configuration at the sulfinyl
sulfur, while the minor isomer has an SS one. In the case
of pivaloylated sulfoxides 14, the same tendency is
observed, both the shielding of the anomeric carbon (87.8
ppm vs 90.8 ppm) as well as the larger non equivalence
(∆ν) of the diastereotopic protons Hpro- and Hpro- (115.6
R
S
vs 47.8 Hz) are indicative of an RS absolute configuration
of the major isomer and an SS absolute configuration of
the minor isomer. These assignments were corroborated
by chemical correlation with a sulfinyl derivative whose
absolute configuration was unambiguously determined
by X-ray analysis (vide infra).
Dia ster eoselective Syn th esis of Am in o a n d Im in o
Su lfin yl Glycosid es. To get a diastereomerically pure
imino sulfoxide, as a stereochemically well-defined S/N
ligand, either a totally diastereoselective process or a
nonselective oxidation leading to sulfinyl glycosides
epimers with a good separation factors was needed. We
were delighted to find that the oxidation36 of the TCP-
protected derivative 2 with m-CPBA in methylene chlo-
ride at -78 °C gave the corresponding sulfoxide 15 in
high yield as a single isomer (Scheme 6).
It is worth mentioning that this is the first example of
totally diastereoselective oxidation of a fully protected
â-thioglycoside with 1,2-trans-diequatorial dispositions.
Opposing to the recent affirmation,6 our results on the
oxidation of imino thioglycosides and on the TCP pro-
tected derivatives, indicate that neither the sense nor the
degree of the diastereoselection in the case of â-thiogly-
R
S
in the case of RS sulfoxides than in the case of SS
sulfoxides.This observation has been rationalized by the
existence of a major conformation stabilized by the exo-
anomeric effect33 in the case of sulfoxides with the R
absolute configuration at the sulfinyl sulfur. On the other
hand, in most of the cases, the anomeric carbon in the
RS sulfoxides is more shielded (around 3 ppm) than in
(29) Pirkle, W. H.; Sikkenga, D. L. J . Chromatogr. 1976, 123, 400.
(30) (a) Buist, P. H.; Marecak, D. M. J . Am. Chem. Soc. 1992, 114,
5073. (b) Buist, P. H.; Behrouzian, B.; MacIsaac, K. D.; Cassel, S.;
Rollin, P.; Imberty, A.; Gautier, C.; Pe´rez, S.; Genix, P. Tetrahedron:
Asymmetry, 1999, 10, 2881.
(31) Deshmukh, M.; Dunach, E.; Kagan, H. B. Tetrahedron Lett.
1984, 25, 3467.
(32) Aucagne, V.; Aversa, M. C.; Baratucci, A., Bonacorsi, P.;
Gianneto, P.; Rollin, P.; Tatibouet, A. J . Org. Chem. 2002, 67, 6925.
(33) Lemieux, R. U.; Pavia, A. A.; Martin, J . C.; wartanabe, K. A.
Can. J . Chem. 1969, 47, 4427. For reviews, see: (a) Deslongchamps,
P. Stereoelectronic Effects in Organic Chemistry; Pergamon: New York,
1983. (b) Kirby, A. J .; The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer: New York, 1983. (c) Travoska, I.; Bleha,
T. Adv. Carbohydr. Chem. Biochem. 1989, 47, 45. (c) J uaristi, E.;
Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton, 1995.
(34) We have observed that this rule is also operative for the
R-thioglycosides.5,6 In this case it is the oxidation of the pro-S lone
pair which maintain the exo-anomeric conformation. As a consequence,
in the reported cases, the anomeric carbons of the SS sulfoxides are
more shielded (around 3 ppm) than in the RS epimer.
(35) For the effect of the orientation of the sulfinyl lone pair on the
chemical shifts of the adjacent carbon, see: Carren˜o, M. C.; Garcia
Ruano, J . L.; Martin, A. M.; Pedregal, C.; Rodriguez, J . H.; Rubio, A.;
Sanchez, J .; Solladie´, G. J . Org. Chem. 1990, 55, 2120 and references
therein.
(36) Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.;
Sofia, M. J . J . Org. Chem. 1996, 61, 8347 and references therein.
1436 J . Org. Chem., Vol. 68, No. 4, 2003

Oxidation of 2-Amino-2-deoxy-1-thio-â-D-glucopyranosides
SCHEME 7a
the sulfur and the nitrogen. In the case of the TCP
derivative 3, the oxidation of the phenyl thioglycoside still
gives the corresponding sulfoxide 22 in high diastereo-
selection (10/1 and 4/1, Table 1, entries 2 and 3).
Surprisingly, in the case of phthalimide derivatives 20
and 21, the diastereoselection is highly dependent on the
substituent of the sulfinyl sulfur, giving rise to good
diastereoselection in the case of the ethyl thioglycoside
20 (entry 4, Table 1) and modest diastereoselection in
the case of the phenyl thioglycoside 21 (see Table 1,
entries 5 and 6). The assignment of the stereochemistry
at the sulfinyl sulfur was done on the basis of the result
of the X-ray analysis, supported by our empirical rule.
Accordingly, the anomeric carbons in the minor isomers
of phenyl sulfinyl glycosides 22 (δ 84.7 ppm) and 24 (δ
86.4) are more shielded than the corresponding carbon
in the major isomers 22 (88.7 ppm) and 24 (89.4 ppm),
which is indicative of an SS absolute configuration in the
major sulfoxides and RS absolute configurations in the
minor sulfoxides. In the case of ethyl sulfinyl glycoside
23, both the shielding of the anomeric carbon (83.4 ppm
vs 85.0 ppm) as well as the larger non equivalence (∆ν)
of the diastereotopic protons Hpro- and Hpro- (158.4 vs
a
Key: (a) m-CPBA, CH2Cl2; (b) NH2(CH2)2NH2, CH3CN/EtOH/
THF, 70 °C; (c) p-MeOC6H4CHO, CuSO4, CH2Cl2 (64%).
cosides are general. Owing to the absence of the other
epimer at sulfur, we could not apply with confidence our
NMR model for the determination of the stereochemistry
of the sulfinyl sulfur of 15, even though the non equiva-
lence (∆ν) of the diastereotopic protons Hpro- and Hpro-
(77 Hz) is indicative of an SS absolute configuration.
Fortunately, compound 15 Ss is crystalline, and we
succeeded in preparing a single crystal suitable for X-ray
crystallographic analysis (see the Supporting Informa-
tion). The absolute configuration at the sulfinyl sulfur
was S, confirming the previous assignment based on our
R
S
R
S
30.5 Hz) are indicative of an RS absolute configuration
of the minor isomer and an SS absolute configuration of
the major isomer.
empirical rule using the proton Hpro- and Hpro-
.
R
S
Due to the diastereocontrol bias exerted by the TCP
group, the access to diastereomerically pure imino sulf-
oxides is thus possible as long as the oxidation of
thioglycosides is conducted at the TCP stage. Accordingly,
oxidation of either 5 or 10 with m-CPBA in methylene
chloride as usual leads to the corresponding sulfoxides
16SS and 17SS almost as a single isomer (see the
Experimental Section) in good yields. Aminolysis with
ethylenediamine as before leads to amino sulfoxides 18SS
and 19SS in acceptable yields.
Imination with p-methoxybenzaldehyde using CuSO4
afforded the desired imino sulfoxides 9SS and 14SS
diastereomerically pure in good yields (Scheme 7). The
obtained SS sulfoxide 9 has the anomeric carbon at 91.1
ppm with a small non equivalence (∆ν) of the diaste-
reotopic protons Hpro- and Hpro- (42.1 Hz). In the same
To ascertain the high diastereoselectivity obtained, it
is necessary to determine the stable conformation at
equilibrium of the starting thioglycoside. While the
conformational studies of thiosaccharides are scarce, it
has been recently shown, by means of NMR (NOE) and
molecular mechanics calculations, that stable conforma-
tions at equilibrium of thiocellobiose are those of the exo-
anomeric effect.37 On the other hand, we and others5,12
have recently invoked the exo-anomeric conformation of
thioglycosides in order to explain their reactivity toward
electrophiles. The crystal structure of compound 15SS
remains that of exo-anomeric conformation of the starting
thioglycoside 2 (see the Supporting Information). Ad-
ditionally, a careful analysis of a large number of the
reported crystalline structure of sulfinyl glycosides in the
literature shows that they all crystallize in the exo-
anomeric conformation.5,12,30b,38 Based on these assump-
tions, we propose that the conformation of the starting
thioglycoside is that of the exo-anomeric effect, Figure
4. In this conformation, the pro-S lone pair (lp) of the
sulfur atom is in a syn relationship with the bulky TCP
group, while the pro-R lp is at the 1,3-diaxial disposition
with regard to the H-2 and the O-5 lp. On the other hand,
the mechanism of oxidation of thioether has been studied
from both kinetic39 and theoretical aspects.40 From the
above studies, the following conclusions, which are of
R
S
manner, sulfoxide 14SS has the anomeric carbon at 90.8
ppm with a small nonequivalence (∆ν) of the diaste-
reotopic protons Hpro- and Hpro- (47.8 Hz) Contrasting
R
S
these data with the H and 13CNMR spectra of the crude
mixture of the oxidation of iminothioglycosides 7 and 12
(vide supra) permits the confirmation of our previous
assignment based on our empirical model.
1
Or igin of th e Dia ster eoselectivity. The unusually
high diastereoselective oxidation of 2, 5, and 10 makes
necessary a detailed study of this transformation. To
determine whether the high diastereoselection observed
is a result of the protective group of the nitrogen atom,
the substituent of the sulfur atom, or both, thioglycosides
20 and 21 were synthesized from the corresponding
anomeric acetate as before and oxidized (Table 1). The
oxidation has been carried out using m-CPBA in meth-
ylene chloride at -78 °C until completion, or stopped at
50% transformation of the thioglycoside (entries 3 and
5), to determine the extent of kinetic resolution. The
(37) Montero, E.; Vallmitjana, M.; Pe´rez-Pons, J . A.; Querol, E.;
J ime´nez-Barbero, J .; Can˜ada, F. J . FEBS Lett. 1998, 421, 243.
(38) It is worth noting that the crystalline sulfoxides reported in
refs 17 and 30 have an RS absolute configuration at the sulfinyl sulfur
and both adopt the conformation with the exo anomeric effect, in spite
an unfavorable gauche relationship between the C1-O5 and the S-O
dipoles.
(39) (a) Davis, F. A.; Billmers, J . M.; Gosciniak, D. J .; Towson, J .
C.; Bach, R. D. J . Org. Chem. 1986, 51, 4240. (b) Overberger, C. G.;
Cummins, R. W. J . Am. Chem. Soc. 1953, 75, 4250. (c) Curci, R.;
DiPrete, R. A.; Edwards, J . O.; Modena, G. J . Org. Chem. 1970, 35,
740. (d) Behrman, E. J . Edwards, J . O. Prog. Phys. Org. Chem. 1967,
4, 93.
1
diastereoselection was always determined by H NMR
analysis of the crude.
As can be seen from Table 1, the diastereoselection is
variable in all cases and depends on both substituent on
(40) Bach, R. D.; Coddens, B. A.; McDouall, J . J . W.; Schlegel, H.
B.; Davis, F. A. J . Org. Chem. 1990, 55, 3325.
J . Org. Chem, Vol. 68, No. 4, 2003 1437

Khiar et al.
TABLE 1a
a
b
All reactions were carried out at -78 °C, in dry CH2Cl2, using 1.05 equiv of m-CPBA. Chemical shift of the anomeric carbon.
c Nonequivalence of the diastereomeric methylenic protons of EtSO. Determined by 1HNMR of the crude. e No trace of the RS isomer
d
was detected by 1H NMR or by 13C NMR analysis of the crude.
oxygen can no be ruled out, to explain the selectivity.41
The modest selectivity observed in the oxidation of the
N-phthalimide phenylthioglycoside 21, can be explained
taking into account that the above charge-transfer com-
plex between the benzene ring of the Pht group and the
ring of mCPBA is less favored. Additionally, one can
propose that in this case, the starting thioglycoside exist
in two different conformations, one stabilized by the exo-
anomeric effect leading to the S diastereoisomer, and
another stabilized by a π-π stacking leading to the R
diastereoisomer.
F IGURE 4. Plausible mechanism of the highly diastereo-
selctive oxidation of thioglycoside 2.
Con clu sion s
interest to our discussion, can be drawn: (a) the peracids
are electrophilic toward sulfides; (b) the oxidations are
second-order reactions (first order for each component);
thus, the transition state contains both peracid and
We have reported on an effective synthetic route to â-D-
2-desoxy-2-imino thioglycosides and to diastereomerically
pure â-D-2-desoxy-2-iminosulfinyl glycosides. Tetrachlo-
rophthalimide-protected 2-amino-2-desoxy-â-D-thiogly-
thioether; (c) by ab initio calculation a model has been
cosides, for which a single high-yielding step has been
proposed where the peracid approaches the sulfur atom
developed, were shown to be excellent intermediates for
along the 3p orbital. Taken together, the model in Figure
these new S/N ligands. The tetrachlorophthalimide group
4 for the transition state of oxidation of thioglycosides
performs different functions in our synthetic design: a
can be drawn.
participating group allowing a stereospecific construction
of a â-thioglycosidic linkage, an orthogonal temporary
amine protective group, and finally, an excellent diaste-
Both steric and stereoelectronic factors can be evoked
to explain the high diastereoselectivity observed. The
known characteristic of the amide to adopt a syn confor-
reocontrol bias allowing the stereoselective synthesis of
mation forces the phthalimide group to be quasi-parallel
a single sulfoxide diastereoisomer. Following our previous
studies on the oxidation of thioglycosides, in the present
work we demonstrate that the oxidation of â-thioglyco-
sides depends on the nature of the protective group of
the amine function. While a single isomer is always
obtained in the case of tetrachlorophthalimide-protected
to the axis of the 3p orbital of the pro-S lp. In this
conformation, the Pht and the TCP group leave a free
space around the pro-S lp facilitating the approach to the
peracid, while the attack of the pro-R lp of the thiogly-
coside is hindered by the O-5 lp, and H-2. From a
stereoelectronic point of view, the parallel positioning of
compounds, a mixture of isomers is obtained in the case
the tetrachlorophthalimide group can stabilize the tran-
of the phthalimide counterpart, and most importantly, a
sition state leading to the S diastereoisomer by a π-π
slightly diastereoselective process in favor of the nonde-
stacking, between the highly electron-deficient benzene
ring of the TCP group and the aromatic ring of the
peracid with higher electrondensity. Additionally, a
(41) In this regard, it is interesting to note that in the crystal
structure of 15SS a water molecule appears hydrogen bonded to one
hydrogen bond between the peracid and the amidic
of the carbonyl oxygens of the tetrachlophthalimide moiety.
1438 J . Org. Chem., Vol. 68, No. 4, 2003

Oxidation of 2-Amino-2-deoxy-1-thio-â-D-glucopyranosides
NMR (CDCl3, 125 MHz) δ 170.6, 170.5, 169.4, 163.2, 162.2,
140.8, 140.6, 133.3, 130.5, 130.1, 129.0, 128.6, 127.1, 126.8,
82.4, 76.0, 71.7, 68.4, 62.1, 54.4, 20.7, 20.6, 20.4.
tected R isomer is observed in the case of imino thiogly-
coside. The diastereoselectivity of â-D-thioglycosides is a
fine balance of steric and stereoelectronic effects. In the
exo-anomeric stabilized conformations of the starting
thioglycosides of the gluco and galacto series, the ap-
proximation of the peracids to the pro-S lp is favored by
hydrogen bonding and π-π stacking as in the case of acyl
protected compounds. In the absence of these stabilizing
factors, as in the case of ether and imine protected
compounds, the approximation to the pro-R lp is favored.
The configuration at the sulfinyl sulfur of all the sulfox-
ides reported in this study has been determined by our
empirical rule using anomeric carbon as well as vicinal
proton to the sulfur chemical shifts as NMR probe. In
all the cases the assignment was corroborated either by
X-ray analysis or by chemical correlation. These new S/N
ligands are actually being used in palladium catalyzed
asymmetric transformations and the results will be
reported in due courses.
1-Eth ylsu lfen yl-1,2-d id eoxy-2-N-tetr a ch lor op h th a lim -
id o-â-D-glu cop yr a n osid e (4). To a mixture of 2 (10 g, 16.7
mmol) in acetone (220 mL) was added a solution of concen-
trated HCl (20 mL) in H2O (71 mL). The reaction was heated
at 70 °C for 1 h, 40 mL of H2O was added, and stirring was
continued overnight. After evaporation of acetone, the aqueous
layer was extracted with AcOEt (4 × 125 mL). The organic
layer was washed successively with saturated NaHCO3 (150
mL) and brine (150 mL), dried (Na2SO4), and evaporated,
giving pure 4 in quantitative yield (7.5 g), which was used in
the next transformations without further purification: mp
1
103-105 °C; H NMR (CDCl3, 500 MHz) δ 5.25 (d, 1H, J )
10.4 Hz), 4.26 (t, 1H, J ) 9.5 Hz), 4.04 (t, 1H, J ) 10.4 Hz),
3.88 (s, 2H), 3.66 (t, 1H, J ) 9.2 Hz), 3.49 (d, 1H, J ) 9.6 Hz),
2.66-2.60 (m, 2H), 1.16 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3,
125 MHz) δ 163.6, 163.2, 140.2, 130.1, 129.6, 127.4, 127.3, 81.1,
79.6, 72.0, 70.8, 61.7, 56.3, 24.6, 14.9; HRMS calcd for C16H15
-
NO6SCl4Na (M + Na)+ 511.9271, found 511.9264 (1.4 ppm).
1-E t h ylsu lfen yl-3,4,6-t r i-O-b en zoyl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (5). To a
solution of 4 (2 g, 4.05 mmol) in dry pyridine (13 mL) were
added benzoyl chloride (2.37 mL, 20.41 mmol) and a catalytic
amount of DMAP (100 mg), and the reaction was stirred for 3
h at room temperature. After evaporation of pyridine, the
residue was diluted with CH2Cl2 (250 mL) and washed with
10% HCl (2 × 100 mL). The aqueous layer was extracted with
CH2Cl2 (4 × 100 mL), and the organic layer was successively
washed with saturated NaHCO3 and brine, dried (Na2SO4),
and evaporated. The crude mixture was purified by flash
column chromatography (AcOEt/Hex, 1:4) giving 5 (2.17 g,
66.17%) as a white solid: mp 145-147 °C; [R]D ) +76.1 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.03-8.01 (m, 2H), 7.90-
7.88 (m, 2H), 7.79-7.77 (m, 2H), 7.56-7.17 (m, 9H), 6.25(dd,
1H, J ) 9.4, 9.9 Hz), 5.72 (t, 1H, J ) 9.5 Hz), 5.65 (d, 1H, J )
10.5 Hz), 4.66-4.61 (m, 2H), 4.52 (dd, 1H, J ) 5.5, 12.2 Hz),
4.28-4.24 (m, 1H), 2.78-2.67 (m, 2H), 1.24 (t, 3H, J ) 7.4
Hz); 13C NMR (CDCl3, 125 MHz) δ 166.0, 165.2, 163.4, 162.4,
140.7, 140.5, 133.6, 133.5, 133.1, 130.1, 129.9, 129.8, 129.7,
129.6, 128.7, 128.6, 128.4, 127.2, 126.9, 81.1, 76.3, 72.0, 69.9,
63.3, 54.7, 24.6, 15.0; HRMS calcd for C37H27NO9SCl4Na (M
+ Na)+ 824.0058, found: 824.0061 (0.3 ppm). Anal. Calcd for
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were run under an atmos-
phere of dry argon using oven-dried glassware and freshly
distilled and dried solvents. THF and diethyl ether were
distilled from sodium benzophenone ketyl. Dichloromethane
was distilled from calcium hydride. TLC was performed on
silica gel with detection by charring with phosphomolybdic
acid/EtOH. For flash chromatography, silica gel (230-400
mesh) was used. Columns were eluted with positive air
pressure. Chromatographic eluents are given as volume-to-
volume ratios (v/v). 1H NMR and 13C NMR spectra were
recorded at 500 and 125 MHz, respectively. Chemical shifts
are reported in ppm, and coupling constants are reported in
Hz. Routine spectra were referenced to the residual proton or
carbon signals of the solvent. The organic extracts were dried
over anhydrous sodium sulfate and concentrated in a vacuum.
1-Eth ylsu lfen yl-3,4,6-tr i-O-a cetyl-1,2-d id eoxy-2-N-tet-
r a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (2). To a mix-
ture of 1 (7.28 g, 11.8 mmol) and ethanethiol (2.2 mL, 29.5
mmol) in methylene chloride (40 mL) was added BF3‚Et2O (6
mL, 65.2 mmol) at room temperature and then heated to
reflux. After 2 h, a TLC analysis of a diluted aliquot showed
the total consumption of 1. The mixture was diluted with
methylene chloride and washed successively with saturated
aqueous sodium bicarbonate (NaHCO3) and brine. The organic
layer was dried (Na2SO4) and concentrated. The crude mixture
was purified over silica gel (EtOAc/Hex 3:7) affording 2 (6.0
g, 82%) as a white solid: mp 147-151 °C; [R]D ) +56.7 (c 0.9,
C
37H27Cl4NO9S: C, 55.31; H, 3.39; N, 1.74. Found: C, 54.95;
H, 3.26; N, 1.99.
1-Eth ylsu lfen yl-1,2-dideoxy-2-am in o-3,4,6-tr i-O-ben zoyl-
â-D-glu cop yr a n osid e (6). To a solution of 5 (693 mg, 1.29
mmol) in 14 mL of a mixture of CH3CN/EtOH/THF (2:1:1) was
added ethylenediamine (0.26 mL, 3.88 mmol), and the mixture
was heated to 70 °C for 3 h. After evaporation of the solvents,
the crude was purified by flash column chromatography
(EtOAc/Hex, 2:7), giving 6 (199 mg, 43%) as a yellow solid:
1
CHCl3); H NMR (CDCl3, 500 MHz) δ 5.72 (dd, 1H, J ) 10.1,
9.1 Hz), 5.41 (d, 1H, J ) 10.6 Hz), 5.16 (dd, 1H, J ) 10.2, 9.1
Hz), 4.34 (t, 1H, J ) 10.4 Hz), 4.27 (dd, 1H, J ) 12.4, 5.0 Hz),
4.14 (dd, 1H, J ) 12.4, 2.3 Hz), 3.82 (dd, 1H, J ) 10.2, 4.9, 2.3
Hz), 2.71-2.60 (m, 2H), 2.08 (s, 3H), 2.01 (s, 3H), 1.88 (s, 3H),
1.20 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 170.7,
170.5, 169.4, 163.2, 162.4, 140.8, 140.6, 130.1, 127.1, 126.8,
80.8, 76.0, 71.6, 68.6, 62.2, 54.4, 24.5, 20.8, 20.6, 20.5, 14.9.
Anal. Calcd for C22H21Cl4NO9S: C, 42.81; H, 3.43; N, 2.27.
Found: C, 42.95; H, 3.16; N, 2.38.
1
mp 51-53 °C; [R]D ) -54.6 (c 0.9, CHCl3); H NMR (CDCl3,
500 MHz) δ 7.98 (d, 2H, J ) 7.2 Hz), 7.94 (d, 2H, J ) 7.2 Hz),
7.87 (d, 2H, J ) 7.2 Hz), 7.53-7.26 (m, 9H), 5.54 (t, 1H, J )
9.5 Hz), 5.49 (t, 1H, J ) 9.5 Hz), 4.58 (m, 2H), 4.46 (dd, 1H, J
) 5.8, 12.1 Hz), 4.09-4.05 (m, 1H), 3.20 (t, 1H, J ) 9.5 Hz),
2.81-2.61 (m, 2H), 1.61(bs, 2H), 1.31 (t, 3H, J ) 7.4 Hz); 13C
NMR (CDCl3, 125 MHz) δ 166.3, 166.1, 165.5, 133.4, 133.3,
133.1, 129.8, 129.7, 129.1, 128.9, 128.4, 87.8, 77.1, 76.1, 69.9,
63.7, 55.9, 24.8, 15.3; HRMS calcd for C29H30NO7S (M + H)+
536.1742, found 536.1734 (1.7 ppm).
1-P h en ylsu lfen yl-3,4,6-tr i-O-a cetyl-1,2-d id eoxy-2-N-tet-
r a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (3). Obtained
using the same procedure as for 2, using 1 (0.59 g, 0.96 mmol),
thiophenol (0.25 mL, 2.4 mmol), and BF3‚Et2O (0.48 mL, 3.84
mmol). The crude mixture was purified over silica gel (EtOAc/
Hex 2:8) affording 3 (0.4 g, 82%) as a white solid: 1H NMR
(CDCl3, 500 MHz) δ 7.40-7.38 (m, 2H), 7.29-7.25 (m, 3H),
5.70 (t, 1H, J ) 9.6 Hz), 5.65 (d, 1H, J ) 10.5 Hz), 5.13 (t, 1H,
J ) 9.5 Hz), 4.32 (t, 1H, J ) 10.3 Hz), 4.26 (dd, 1H, J ) 12.3,
5.2 Hz), 4.18 (dd, 1H, J ) 12.2, 2.1 Hz), 3.85 (ddd, 1H, J )
10.1, 5.1, 2.2 Hz), 2.08 (s, 3H), 2.01 (s, 3H), 1.86 (s, 3H); 13C
1-Eth ylsu lfen yl-1,2-d id eoxy-2-p-m eth oxyben zylid en e-
a m in o-3,4,6-tr i-O-ben zoyl-â-D-glu cop yr a n osid e (7). To a
mixture of 6 (85 mg, 0.159 mmol) and CuSO4 (71 mg) in CH2-
Cl2 (3 mL) was added p-anisaldehyde (39 µL, 0.036 mmol).
After 12 h, the mixture was filtered over Celite, the solvent
was evaporated, and the residue was purified by flash column
chromatography (Et2O/Hex 1:1), using silica gel pretreated
with 1% NEt3, affording 7 (63 mg, 61%) as a white solid: mp
1
66-68 °C; [R]D ) +45.0 (c 0.3, CHCl3); H NMR (CDCl3, 500
J . Org. Chem, Vol. 68, No. 4, 2003 1439

Khiar et al.
MHz) δ 8.13 (s, 1H), 7.99 (d, 2H, J ) 7.6 Hz), 7.90 (d, 2H, J )
7.6 Hz), 7.77 (d, 2H, J ) 7.6 Hz), 7.54 (d, 2H, J ) 8.7 Hz),
7.53-7.25 (m, 9H), 6.81 (d, 2H, J ) 8.7 Hz), 5.88 (t, 1H, J )
9.4 Hz), 5.62 (t, 1H, J ) 9.8 Hz), 5.07 (d, 1H, J ) 9.8 Hz), 4.61
(dd, 1H, J ) 3.0, 12.0 Hz), 4.52 (dd, 1H, J ) 6.0, 12.0 Hz),
4.23-4.19 (m, 1H), 3.75 (s, 3H), 3.59 (t, 1H, J ) 9.5 Hz), 2.80-
2.27 (m, 2H), 1.27 (t, 1H, J ) 7.3 Hz); 13C NMR (CDCl3, 125
MHz) δ 166.1, 165.6, 165.3, 163.8, 162.0, 133.3, 133.0, 130.2,
129.8, 129.7, 129.5, 129.3, 129.0, 128.4, 128.3, 128.2, 113.9,
84.8, 76.2, 74.8, 74.5, 70.0, 63.9, 55.3, 24.9, 15.0; HRMS calcd
for C37H36NO8S (M + H)+ 654.2161, found 654.2129 (4.9 ppm).
Hex, 1:9) giving 10 (1.78 g, 56%) as a yellow solid: mp 87-90
°C; [R]D ) +36.7 (c 0.9, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
5.74 (t, 1H, J ) 9.6 Hz), 5.48 (d, 1H, J ) 10.6 Hz), 5.20 (t, 1H,
J ) 9.7 Hz), 4.36 (t, 1H, J ) 10.4 Hz), 4.25 (dd, 1H, J ) 12.3,
1.3 Hz), 4.09 (dd, 1H, J ) 12.3, 5.8 Hz), 3.88-3.84 (m, 1H),
2.73-2.68 (m, 1H), 2.67-2.62 (m, 1H), 1.25-1.22 (m, 12H),
1.17 (s, 9H), 0.94 (s, 9H); 13C NMR (CDCl3, 50 MHz) δ 178.0,
177.9, 176.4, 163.2, 162.4, 140.7, 140.4, 130.1, 129.9, 127.1,
126.8, 80.5, 76.6, 71.2, 67.9, 62.2, 54.6, 38.9, 38.8, 38.7, 27.1,
27.0, 24.3, 15.0; HRMS calcd for C31H39Cl4NO9SNa (M + Na)+
764.0997, found 764.1002 (0.7 ppm). Anal. Calcd for C31H39
-
P a lla d iu m Com p lex: 7‚P d Cl2 (8). A solution of 7 (22.5
mg, 0.034 mmol) in dry deoxygenated CH2Cl2 (5 mL) in a
Schlenk flask was treated with PdCl2(CH3CN)2 (8.58 mg, 0.033
mmol) under argon atmosphere. After 1 h, the solvent was
removed by vacuum and the residue obtained washed three
times with dry deoxygenated diethyl ether, affording 8 as
yellow orange solid in 80% yield, as a 2.5:1 epimer mixture.
Cl4NO9S: C, 50.08; H, 5.29; N, 1.88. Found: C, 50.10; H, 5.19;
N, 1.94.
1-Eth ylsu lfen yl-3,4,6-tr i-O-pivaloyl-1,2-dideoxy-2-am in o-
â-D-glu cop yr a n osid e (11). To a solution of 10 (538 mg, 0.73
mmol) in 8 mL of a mixture of CH3CN/EtOH/THF (2:1:1) was
added ethylenediamine (0.2 mL, 3.27 mmol), and the mixture
was heated to 70 °C for 8 h. After evaporation of the solvents,
the crude was purified by flash column chromatography
(EtOAc/Hex, 2:7), giving 11 (142 mg, 41%) as a yellow solid:
mp 106-109 °C; [R]D ) -8.6 (c 0.4, MeOH); 1H NMR (CDCl3,
500 MHz) δ 5.05-4.99 (m, 2H), 4.33 (d, 1H, J ) 9.9 Hz), 4.20
(d, 1H, J ) 12.0 Hz), 4.02 (dd, 1H, J ) 6.1, 12.2 Hz), 3.71-
3.69 (m, 1H), 2.92 (t, 1H, J ) 9.5 Hz), 2.72 (AB fragment of
an ABX3 system, 2H, ∆υ ) 31 Hz, J ) 7.3, 12.8 Hz), 1.40 (broad
s, 2H), 1.30 (t, 3H, J ) 7.3 Hz), 1.20, 1.17 and 1.15 (3s, 27H);
13C NMR (CDCl3, 50 MHz) δ 178.0, 177.8, 176.7, 87.3, 76.4,
76.1, 68.1, 62.6, 55.8, 38.9, 38.8, 38.7, 27.2, 27.1, 24.4, 15.2;
HRMS calcd for C23H41NO7S (M)+ 475.2603, found 475.2615
(2.4 ppm). Anal. Calcd for C23H41NO7S: C, 58.08; H, 8.69; N,
2.94. Found: C, 58.26; H, 8.28; N, 2.89.
1
Ma jor isom er : H NMR (CDCl3, 500 MHz) δ 8.39-8.38 (m,
3H), 8.05-7.19 (m, 15H), 6.70 (d, 2H, J ) 8.7 Hz), 6.53 (t, 1H,
J ) 9.4 Hz), 5.84 (t, 1H, J ) 9.5 Hz), 5.32 (t, 1H, J ) 9.5 Hz),
5.12 (d, 1H, J ) 10.2 Hz), 4.62-4.60 (m, 1H), 4.56 (d, 1H, J )
12.5 Hz), 4.41 (dd, 1H, J ) 3.8, 12.5 Hz), 3.72 (s, 3H), 3.21-
3.04 (m, 2H), 1.61 (t, 3H, J ) 7.5 Hz). Min or isom er : 1H NMR
(CDCl3, 500 MHz) δ 8.54 (d, 2H, J ) 8.2 Hz), 8.33 (s, 1H),
8.05-7.19 (m, 15H), 6.88 (d, 2H, J ) 8.8 Hz), 6.27 (t, 1H, J )
9.5 Hz), 5.80 (t, 1H, J ) 9.5 Hz), 5.43(t, 1H, J ) 9.5 Hz), 4.84-
4.78 (m, 2H), 4.39-3.82 (m, 2H), 3.80 (s, 3H), 3.40-3.38 (m,
2H), 1.61 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3, 50 MHz)
spectroscopic data for the mixture of both isomers, δ 169.8,
166.6, 166.0, 164.9, 164.7, 135.2, 134.9, 134.4, 133.8, 133.6,
133.2, 130.2, 129.8, 129.7, 128.8, 128.4, 127.5, 123.6, 114.0,
113.8, 87.5, 86.4, 83.0, 76.4, 74.9, 71.2, 70.7, 69.1, 68.8, 62.3,
61.6, 55.6, 33.9, 30.3, 14.9.
1-Eth ylsu lfen yl-1,2-d id eoxy-2-p-m eth oxyben zylid en e-
a m in o-3,4,6-tr i-O-p iva loyl-â-D-glu cop yr a n osid e (12). To a
mixture of 11 (70 mg, 0.147 mmol) and CuSO4 (70 mg) in CH2-
Cl2 (5 mL) was added p-anisaldehyde (36 µL, 0.036 mmol).
After 12 h, the solvent was evaporated and the mixture was
purified by flash column chromatography (Et2O/Hex, 3:7),
using silica gel pretreated with 1% NEt3, affording 12 (56 mg,
64%) as a white solid: mp 101-102 °C; [R]D ) +36.2 (c 0.6,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.1 (s, 1H), 7.62 (d, 2H,
J ) 8.2 Hz), 6.88 (d, 2H, J ) 8.6 Hz), 5.44 (t, 1H, J ) 9.4 Hz),
5.11 (t, 1H, J ) 9.8 Hz), 4.88 (d, 1H, J ) 9.8 Hz), 4.26 (dd, 1H,
J ) 1.4, 12.1 Hz), 4.08 (dd, 1H, J ) 6.3, 12.1 Hz), 3.87-3.83
(m, 1H), 3.82 (s, 3H), 3.35 (t, 1H, J ) 9.8 Hz), 2.69 (AB
fragment of an ABX3 system, 2H, ∆υ ) 31 Hz, J ) 7.3, 12.8
1-(R)- a n d 1-(S)-E t h ylsu lfin yl-1,2-d id eoxy-2-p-m et h -
oxyben zylid en ea m in o-3,4,6-tr i-O-ben zoyl-â-D-glu cop yr a -
n osid e (9). To a solution of 7 (22.5 mg, 0.036 mmol) in CH2Cl2
(4 mL) at -78 °C was added a solution of m-CPBA (0.036
mmol) in CH2Cl2 (3 mL) via cannula. After 1 h, the reaction
was stopped by addition of saturated sodium bisulfite and
diluted with CH2Cl2 (40 mL). The organic layer was washed
with NaHCO3, and the aqueous layer was further extracted
with CH2Cl2 (4 × 50 mL). The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The crude mixture was
purified by flash column chromatography (EtOAc/Hex, 9:1)
affording 9 (80% yield) as a 65:35 mixture of both epimers at
sulfur. Diastereoisomer 9RS was obtained as the major dia-
stereomer: 1H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H), 7.98 (d,
2H, J ) 7.5 Hz), 7.91 (d, 2H, J ) 7.6 Hz), 7.80 (d, 2H, J ) 7.4
Hz), 7.57-7.26 (m, 11H), 6.82 (d, 2H, J ) 8.6 Hz), 5.99 (t, 1H,
J ) 9.6 Hz), 5.64 (t, 1H, J ) 9.8 Hz), 4.66 (dd, 1H, J ) 3.0,
12.2 Hz), 4.60 (dd, 1H, J ) 6.7, 12.1 Hz), 4.56 (d, 1H, J ) 9.9
Hz), 4.32-4.27 (m, 1H), 4.23 (t, 1H, J ) 9.7 Hz), 3.79 (s, 3H),
3.17-3.13 (m 1H), 2.94-2.89 (m 1H), 1.25 (t, 1H, J ) 7.5 Hz);
13C NMR (CDCl3, 125 MHz, taken from a mixture of both
epimers at sulfur) δ 166.4, 165.4, 162.3, 133.4, 133.1, 130.4,
129.9, 129.8, 129.5, 128.4, 128.2, 113.9, 88.3, 77.4, 74.4, 69.7,
68.2, 63.7, 55.3, 41.2, 7.2.
Hz), 1.26 (t, 3H, J ) 7.4 Hz), 1.22, 1.15 and 0.96 (3s, 27H); 13
C
NMR (CDCl3, 50 MHz) δ 178.1, 176.9, 176.5, 163.6, 162.1,
130.3, 128.3, 114.0, 84.2, 76.5, 74.8, 73.8, 68.1, 62.7, 55.4, 38.9,
38.8, 38.6, 27.3, 27.2, 27.1, 24.6, 15.0; HRMS calcd for C31H47
-
NO8S (M)+ 593.3022, found 593.3005 (2.8 ppm). Anal. Calcd
for C31H47NO8S: C, 62.71; H, 7.98; N, 2.36. Found: C, 62.54;
H, 8.02; N, 2.11.
P a lla d iu m Com p lex: 12‚P d (Cl)2 (13). A solution of 12
(54 mg, 0.091 mmol) in dry deoxygenated CH2Cl2 (5 mL) in a
Schlenk flask was treated with PdCl2(CH3CN)2 (23 mg, 0.091
mmol) under argon atmosphere. After 1 h, the solvent was
removed by vacuum and the residue obtained washed three
times with dry deoxygenated diethyl ether, affording 13 as
yellow orange solid in 80% yield and as a 1:0.8 epimers
mixture. Spectroscopical data were taken from the mixture of
both diastereoisomers: 1H NMR (CDCl3, 500 MHz) δ major
isomer 8.60 (d, 2H, J ) 8.3 Hz), 7.96 (s, 1H), 7.04 (d, 2H, J )
8.3 Hz), 5.74 (t, 1H, J ) 9.3 Hz), 5.29-5.23 (m, 1H), 4.89 (t,
1H, J ) 9.3 Hz), 4.43 (d, 1H, J ) 10.4 Hz), 4.26-4.08 (m, 2H),
3.90-3.89 (m, 4H), 3.08-3.02 (m, 2H), 1.58 (t, 3H, J ) 7.2
Hz), 1.23, 1.16, 1.14 (3s, 27H); minor isomer 8.60 (d, 2H, J )
8.3 Hz), 7.89 (s, 1H), 7.02 (d, 2H, J ) 8.3 Hz), 5.69 (t, 1H, J )
9.3 Hz), 5.31-5.23 (m, 2H), 4.49 (d, 1H, J ) 9.9 Hz), 4.26-
4.08 (m, 2H), 3.90-3.89 (m, 4H), 3.52-3.47 (m, 2H), 1.74 (t,
3H, J ) 7.2 Hz), 1.23, 1.16, 1.14 (3s, 27H); 13C NMR (CDCl3,
50 MHz) both isomers δ 177.9, 177.6, 176.5, 176.1, 168.8, 168.5,
The minor diastereomer 9SS has the same physical data as
that obtained optically pure from the imination of 18SS (vide
infra).
1-E t h ylsu lfen yl-3,4,6-t r i-O-p iva loyl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (10). To a
solution of 4 (2 g, 4.05 mmol) in dry pyridine (13 mL) were
added pivaloyl chloride (3 mL, 24.4 mL) and a catalytic amount
of DMAP (100 mg), and the reaction was refluxed for 60 h.
After evaporation of pyridine, the residue was diluted with
CH2Cl2 (250 mL) and washed with 10% HCl (2 × 100 mL).
The aqueous layer was extracted with CH2Cl2 (4 × 100 mL),
and the organic layer was successively washed with saturated
NaHCO3 and brine, dried (Na2SO4), and evaporated. The crude
mixture was purified by flash column chromatography (AcOEt/
1440 J . Org. Chem., Vol. 68, No. 4, 2003

Oxidation of 2-Amino-2-deoxy-1-thio-â-D-glucopyranosides
165.3, 134.8, 123.3, 114.1, 114.0, 87.6, 78.1, 77.8, 75.3, 69.3,
69.0, 67.1, 66.8, 61.2, 60.9, 55.8, 39.0, 38.8, 26.8, 26.7, 26.6,
14.7.
140.5, 133.7, 133.4, 130.2, 129.9, 129.7, 129.3, 128.7, 128.5,
128.4, 128.2, 127.1, 84.0, 77.3, 71.1, 69.3, 62.6, 53.3, 43.8, 5.7;
HRMS calcd for C37H27NO10SCl4Na (M + Na)+ 840.0007, found
840.0050 (5.1 ppm).
1-(R)- a n d 1-(S)-E t h ylsu lfin yl-1,2-d id eoxy-2-p-m et h -
oxyben zylid en ea m in o-3,4,6-tr i-O-p iva loyl-â-D-glu cop yr a -
n osid e (14). To a solution of 12 (24.7 mg, 0.042 mmol) in
CH2Cl2 (4 mL) at -78 °C was added a solution of m-CPBA
(0.042 mmol) in CH2Cl2 (3 mL) via cannula. After 1 h, the
reaction was stopped by addition of saturated sodium bisulfite
and diluted with CH2Cl2 (40 mL). The organic layer was
washed with NaHCO3, and the aqueous layer was further
extracted with CH2Cl2 (4 × 50 mL). The organic layer was
washed with brine, dried (Na2SO4), and evaporated. The crude
mixture of 14 was shown by NMR to be a 55:45 mixture of
both epimers at sulfur. Diastereoisomer 14RS was the major
diastereomer (see text): 1H NMR (CDCl3, 500 MHz) δ 8.34 (s,
1H), 7.63 (d, 2H, J ) 8.6 Hz), 6.89 (d, 1H, J ) 8.6 Hz), 5.54 (t,
1H, J ) 9.5 Hz), 5.14 (t, 1H, J ) 9.7 Hz), 4.39-4.34 (m, 2H),
4.09-4.07 (m, 1H), 4.00-3.93 (m, 2H), 3.83 (s, 3H), 3.14-3.07
(m, 1H), 2.92-2.98 (m, 1H), 1.28-1.23 (m, 12H), 1.14 (s, 3H),
0.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.9, 176.7, 176.5,
165.6, 162.3, 130.3, 128.1, 114.1, 87.9, 77.7, 68.9, 67.2, 61.8,
40.9, 31.6, 29.7, 27.1, 22.6, 14.1.
1-(S)-Eth ylsu lfin yl-3,4,6-tr i-O-p iva loyl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (17SS). To
a solution of 10 (1.22 g, 1.65 mmol), in dry CH2Cl2 (10 mL),
was added a solution of 70% of m-CPBA (426 mg, 1.73 mmol)
in CH2Cl2 (6 mL) at -78 °C. The reaction was instantaneous
and stopped after 15 min by addition of saturated sodium
sulfite and diluted with CH2Cl2. The organic layer was washed
with NaHCO3, the aqueous layer was further extracted with
CH2Cl2 (4 × 50 mL), and the organic layer was washed with
brine, dried (Na2SO4), and evaporated. The 1HNMR spectra
of the crude shows mainly the desired product 17SS (>90%)
with a small amount of other compound which could not be
isolated (<10%). The crude mixture was purified by flash
column chromatography (EtOAc/Hex, 1:4), affording 17SS (984
mg, 79%) as a white solid: mp 169-172 °C; [R]D ) +77.8 (c
1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.89 (t, 1H, J ) 9.7
Hz), 5.21(t, 1H, J ) 9.7 Hz), 5.09 (d, 1H, J ) 10.5 Hz), 4.80 (t,
1H, J ) 10.3 Hz), 4.26 (dd, 1H, J ) 1.1, 12.3 Hz), 4.06 (dd,
1H, J ) 5.9, 12.5 Hz), 3.95-3.93 (m, 1H), 2.85 (AB fragment
of an ABX3 system, 2H, ∆υ) 86 Hz, J ) 7.3, 7.6, 13.4 Hz),
1.30 (t, 3H, J ) 7.5 Hz), 1.25, 1.15 and 1.00 (3s, 27H); 13C NMR
(CDCl3, 50 MHz) δ 178.0, 177.9, 176.4, 163.2, 162.4, 140.8,
140.5, 130.1, 129.9, 127.1, 126.8, 86.0, 80.5, 76.6, 71.3, 67.9,
62.2, 54.6, 38.9, 38.8, 38.7, 27.1, 27.0, 24.3, 17.6, 15.0; HRMS
The minor diastereomer 14SS has the same physical data
than that obtained optically pure from the imination of 19SS
(vide infra).
1-(S)-E t h ylsu lfin yl-3,4,6-t r i-O-a cet yl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (15SS). To
a solution of 2 (1.29 g, 2 mmol) in CH2Cl2 (40 mL) at -78 °C
was added a solution of m-CPBA (2.1 mmol) in CH2Cl2 (4 mL)
via cannula. After 1 h, the reaction was stopped by addition
of saturated sodium bisulfite and diluted with CH2Cl2 (250
mL). The organic layer was washed with NaHCO3, and the
aqueous layer was further extracted with CH2Cl2 (4 × 50 mL).
The organic layer was washed with brine, dried (Na2SO4), and
evaporated. The crude mixture can be purified by flash column
chromatography (EtOAc/Hex, 1:4) or recrystallized from EtOAc/
Hex, affording pure 15SS (89%) as a white solid: mp 149-
152 °C; [R]D ) +104.7 (c 0.9, CHCl3); 1H NMR (CDCl3, 500
MHz) δ: 5.88 (t, 1H, J ) 9.5 Hz), 5.17 (t, 1H, J ) 9.6 Hz),
5.02 (d, 1H, J ) 10.5 Hz), 4.80 (t, 1H, J ) 10.5 Hz), 4.26 (dd,
1H, J ) 12.5, 4.9 Hz), 4.17 (dd, 1H, J ) 2.0, 12.5 Hz), 3.92 (m,
1H), 2.94 (m, 1H), 2.78 (m, 1H), 2.09 (s, 3H), 1.92 (s, 3H), 1.3
(t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3, 50 MHz) δ 170.4, 170.3,
169.3, 140.6, 130.2, 127.1, 83.9, 70.8, 68.1, 67.8, 61.5, 52.9, 43.7,
20.7, 20.6, 20.5, 5.8; HRMS calcd for C22H21Cl4NO10SNa (M +
Na)+ 653.9538, found 653.9544 (0.9 ppm). Anal. Calcd for
calcd for
C
31H39NO10SCl4Na (M + Na)+ 780.0946, found
780.0992 (5.9 ppm). Anal. Calcd for C31H39Cl4NO10S: C,49.02;
H, 5.18; N, 1.84. Found: C, 50.13; H, 5.40; N, 2.30.
1-(S)-Eth ylsu lfin yl-1,2-dideoxy-2-am in o-3,4,6-tr i-O-ben -
zoyl-â-D-glu cop yr a n osid e (18SS). To a solution of 16SS (752
mg, 0.919 mmol) in 15 mL of a mixture of solvents CH3CN/
EtOH/THF (2:1:1) was added ethylendiamine (0.28 mL, 4.137
mmol). After 3 h at reflux, the mixture was evaporated to
dryness and purified by flash column chromatography (Et2O/
Hex, 1:1) affording 18SS (177 mg, 34%) as a slightly yellow
solid: mp 79-81 °C; [R]D ) -26.0 (c 0.8, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.98 (d, 2H, J ) 7.2 Hz), 7.93 (d, 2H, J )
7.2 Hz), 7.87 (d, 2H, J ) 7.2 Hz), 7.55-7.26 (m, 9H), 5.59-
5.52 (m, 2H), 4.56 (dd, 1H, J ) 2.8, 12.3 Hz), 4.44 (dd, 1H, J
) 5.6, 12.3 Hz), 4.28 (d, 1H, J ) 9.7 Hz), 4.15-4.11 (m, 1H),
3.76(t, 1H, J ) 9.3 Hz), 2.98 (c, 2H, J ) 7.5 Hz), 1.92 (bs, 2H),
1.34 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 166.3,
166.0, 165.4, 133.5, 133.3, 129.8, 129.7, 128.9, 128.7, 128.4,
91.6, 76.8, 69.0, 63.0, 54.0.9, 43.9, 6.2; HRMS calcd for C29H29
-
NO8SNa (M + Na)+ 574.1511, found 574.1506 (0.5 ppm).
C
22H21Cl4NO10S: C, 41.72; H, 3.34; N, 2.21. Found: C, 41.80;
H, 2.96; N, 2.28.
1-(S)-E t h ylsu lfin yl-1,2-d id eoxy-2-p -m et h oxyb en zyli-
d en ea m in o-3,4,6-tr i-O-ben zoyl-â-D-glu cop yr a n osid e (9SS)
Obta in ed fr om 18SS. To a mixture of 18SS (145 mg, 0.256
mmol) and CuSO4 (140 mg) in dry CH2Cl2 (9 mL) was added
p-anisaldehyde (62 µL, 0.51 mmol). After the mixture was
stirred for 24 h, the solvent was evaporated and the mixture
was purified by flash column chromatography (EtOAc/Hex,
1:1), using silica gel pretreated with 1% NEt3, affording 9SS
in 83% yield as a white solid: mp 76-78 °C; [R]D ) +24.8 (c
1-(S)-Eth ylsu lfin yl-3,4,6-tr i-O-ben zoyl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (16SS). To
a solution of 7 (1.1 g, 1.36 mmol), in CH2Cl2 (10 mL), was added
a solution of 70% of m-CPBA (354 mg, 1.43 mmol) in CH2Cl2
(6 mL) at -78 °C. The reaction was instantaneous and stopped
after 15 min by addition of saturated sodium sulfite and
diluted with CH2Cl2. The organic layer was washed with
NaHCO3, the aqueous layer was further extracted with CH2-
Cl2 (4 × 50 mL), and the organic layer was washed with brine,
dried (Na2SO4), and evaporated. Depending on the run, the
1HNMR spectra of the crude shows only the desired product
16SS, or together with small amount (<10%) of the sulfone
and another compound. The crude mixture was purified by
flash column chromatography (EtOAc/Hex, 1:2), affording 16SS
(880 mg, 79%) as a white solid: mp 93-94 °C; [R]D ) +51.6 (c
0.3, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.02 (d, 2H, J ) 7.1
Hz), 7.90 (d, 2H, J ) 7.1 Hz), 7.80 (d, 2H, J ) 7.1 Hz), 7.60-
7.26 (m, 9H), 6.41 (t, 1H, J ) 9.7 Hz), 5.71(t, 1H, J ) 9.7 Hz),
5.20 (d, 1H, J ) 10.4 Hz), 5.09 (t, 1H, J ) 10.4 Hz), 4.62 (dd,
1H, J ) 2.6, 12.4 Hz), 4.50 (dd, 1H, J ) 5.7, 12.4 Hz), 4.34-
4.30 (m, 1H), 2.89 (AB fragment of an ABX3 system, 2H, ∆υ )
73 Hz, J ) 7.3, 7.5, 13.5 Hz), 1.30 (t, 3H, J ) 7.5 Hz); 13C
NMR (CDCl3, 125 MHz) δ 171.2, 171.1, 165.9, 165.8, 165.1,
1
0.8, CHCl3); H NMR (CDCl3, 500 MHz) δ: 8.24 (s, 1H), 8.01
(d, 2H, J ) 7.4 Hz), 7.89 (d, 2H, J ) 7.4 Hz), 7.79 (d, 2H, J )
7.4 Hz), 7.55-7.26 (m, 11H), 6.80 (d, 2H, J ) 8.6 Hz), 5.89 (t,
1H, J ) 9.3 Hz), 5.68 (t, 1H, J ) 9.7 Hz), 4.87 (d, 1H, J ) 9.3
Hz), 4.66 (dd, 1H, J ) 2.7, 12.2 Hz), 4.52 (dd, 1H, J ) 5.1,
12.2 Hz), 4.30-4.25 (m, 2H), 3.78 (s, 3H), 2.97-2.93 (m 1H),
2.86-2.82 (m 1H), 1.26 (m, 3H); 13C NMR (CDCl3, 125 MHz)
δ 166.1, 165.7, 165.3, 162.3, 133.4, 133.1, 130.2, 129.8, 129.7,
129.6, 129.5, 129.1, 128.9, 128.4, 128.3, 128.1, 114.0, 91.1, 77.0,
74.3, 69.1, 68.3, 63.2, 55.3, 42.7, 7.3; HRMS calcd for C37H35
-
NO9SNa (M + Na)+ 692.1930, found 692.1893 (5.4 ppm).
1-(S)-E t h ylsu lfin yl-3,4,6-t r i-O-p iva loyl-1,2-d id eoxy-2-
a m in o-â-D-glu cop yr a n osid e (19SS). To a solution of 17SS
(834 mg, 1.11 mmol) in 16 mL of a mixture of solvents CH3-
CN/EtOH/THF (2:1:1) was added ethylendiamine (0.33 mL).
J . Org. Chem, Vol. 68, No. 4, 2003 1441

Khiar et al.
After 3 h at reflux, the mixture was evaporated to dryness
and purified by flash column chromatography (EtOAc/Hex, 3:2)
affording 19SS (294 mg, 54%) as a slightly yellow solid: mp
118-120 °C; [R]D ) -22.3 (c 0.1, MeOH); 1H NMR (CDCl3,
500 MHz) δ 5.08-5.01 (m, 2H), 4.20 (d, 1H, J ) 12.1 Hz), 4.06
(d, 1H, J ) 9.7 Hz), 3.98 (dd, 1H, J ) 5.5, 12.4 Hz), 3.77-3.74
(m, 1H), 3.47 (t, 1H, J ) 9.4 Hz), 2.97-2.91 (m, 2H), 1.70
(broad s, 2H), 1.35 (t, 3H, J ) 7.5 Hz), 1.18, 1.17 and 1.13 (3s,
27H); 13C NMR (CDCl3, 50 MHz) δ 177.8, 176.6, 91.4, 76.8,
75.7, 67.2, 61.8, 54.8, 43.7, 38.9, 38.8, 38.7, 27.2, 27.1, 27.0,
6.1; HRMS calcd for C23H42NO8S (M + H)+ 492.2631, found
492.2635 (0.8 ppm).
1-(S)-E t h ylsu lfin yl-1,2-d id eoxy-2-p -m et h oxyb en zyli-
den eam in o-3,4,6-tr i-O-pivaloyl-â-D-glu copyr an oside (14SS)
Obta in ed by Im in a tion of 19SS. To a mixture of 19SS (294
mg, 0.6 mmol) and CuSO4 (250 mg) in dry CH2Cl2 (16 mL)
was added p-anisaldehyde (146 µL, 1.2 mmol). After being
stirred 12 h, the solvent was evaporated and the mixture was
purified by flash column chromatography (EtOAc/Hex, 2:1),
using silica gel pretreated with 1% NEt3, affording 14SS in
71% yield as a white solid: mp 164-166 °C; [R]D ) -17 (c 0.7,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.24 (s, 1H), 7.61 (d,
2H, J ) 8.6 Hz), 6.89 (d, 1H, J ) 8.6 Hz), 5.46 (t, 1H, J ) 9.4
Hz), 5.19 (t, 1H, J ) 9.8 Hz), 4.68 (d, 1H, J ) 9.5 Hz), 4.27 (d,
1H, J ) 12.3 Hz), 4.15 (dd, 1H, J ) 4.7, 12.4 Hz), 3.98 (t, 1H,
J ) 9.4 Hz), 3.94-3.92 (m, 1H), 3.83 (s, 3H), 2.92-2.84 (m,
1H), 2.80-2.73 (m, 1H), 1.26-1.23 (m, 12H), 1.14 (s, 3H), 0.98
(s, 3H); 13C NMR (CDCl3, 50 MHz) δ 178.0, 176.8, 176.7, 166.3,
162.4, 130.4, 128.1, 114.1, 90.8, 73.3, 68.4, 67.8, 62.6, 55.4,
42.2, 38.9, 38.8, 27.1, 17.0, 7.5; HRMS calcd for C31H48NO9S
(M + H)+ 610.3049, found 610.3051 (0.2 ppm).
3.83 (m, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.88 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 170.6, 170.5, 169.2, 163.0, 162.0, 140.4,
140.0, 131.9, 128.9, 126.8, 125.0, 124.4, 88.7, 76.6, 71.6, 67.8,
61.7, 48.8, 20.7, 20.5, 20.4.
1-P h e n ylsu lfin yl-3,4,6-t r i-O-a ce t yl-1,2-d id e oxy-2-N -
p h th a lim id o-â-D-glu cop yr a n osid e (24). Oxidation of the
known 21 using the same procedure used to oxidize 2, afforded
24 in quantitative yield as 3:1 mixture. Ma jor d ia ster eom er
(24SS): 1H NMR (CDCl3, 500 MHz) δ 7.82-7.26 (m, 4H), 5.92
(t, 1H, J ) 9.3 Hz), 5.21-5.11 (m, 2H), 4.74 (t, 1H, J ) 10.4
Hz), 4.36-4.13 (m, 2H), 3.97-3.94 (m, 1H), 2.95-2.70 (m, 2H),
2.07 (s, 3H), 2.01 (s, 3H), 1.86 (s, 3H), 1.28 (t, 3H, J ) 7.5 Hz);
13C NMR (CDCl3, 125 MHz) δ:170.4, 169.9, 169.3, 134.5, 134.3,
131.4, 123.8, 85.1, 70.8, 68.4, 61.6, 51.9, 43.0, 29.6, 20.6, 20.5,
20.4, 6.0. Min or d ia ster eom er (24RS): 1H NMR (CDCl3, 500
MHz) δ 7.80-7.70 (m, 4H), 5.81 (t, 1H, J ) 9.3 Hz), 5.21-
5.10 (m, 2H), 4.88 (t, 1H, J ) 10.4 Hz), 4.36-4.13 (m, 2H),
3.97-3.94 (m, 1H), 3.12-3.05 (m, 1H), 2.82-2.70 (m, 1H), 2.07
(s, 3H), 2.01 (s, 3H), 1.86 (s, 3H), 1.28 (t, 3H, J ) 7.5 Hz); 13
C
NMR (CDCl3, 125 MHz) δ 170.3, 169.2, 134.5, 134.3, 131.4,
123.8, 83.8, 71.5, 68.4, 62.0, 49.3, 41.2, 29.6, 20.7, 20.5, 20.4,
7.2.
Ack n ow led gm en t. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica for financial sup-
port (Grant No. PB PPQ 2000-1341 and BQU2001-2425)
and Ms. Inmaculada Romero Luque for experimental
help. We are grateful to the Bruker-CSIC Excellence
Centre of the Instituto de Ciencia de Materiales de
Arago´n for the acquisition and preliminary treatment
of the X-ray diffraction data of 15S.
1-(S)-P h en ylsu lfin yl-3,4,6-tr i-O-a cetyl-1,2-d id eoxy-2-N-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (22SS). Oxi-
dation of 3 using the same procedure as that used for the
synthesis of 15SS afforded 22 in quantitative yield as a 10:1
Su p p or tin g In for m a tion Ava ila ble: X-ray structural
data of sulfinyl glycoside 15S and NMR spectra of compounds
3, 8, 9R/S, 13, 14R/S, 17SS, 9SS, 14SS, 9SS, 14SS, 22, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
mixture. Ma jor d ia ster eom er (22SS): H NMR (CDCl3, 500
MHz) δ 7.48-7.47 (m, 2H), 7.27-7.25 (m, 2H), 7.17-7.14 (m,
1H), 5.70 (t, 1H, J ) 9.6 Hz), 5.27 (d, 1H, J ) 10.2 Hz), 5.16
(dd, 1H, J ) 9.4, 10.1 Hz), 4.93 (t, 1H, J ) 10.1 Hz), 4.24 (dd,
1H, J ) 5.0, 12.5 Hz), 4.15 (dd, 1H, J ) 2.0, 12.4 Hz), 3.86-
J O026519Q
1442 J . Org. Chem., Vol. 68, No. 4, 2003