Stereoselective formation of glycosyl sulfoxides and their subsequent equilibration: Ring inversion of an α-xylopyranosyl sulfoxide dependent on the configuration at sulfur

Article abstract of DOI:10.1021/ja0122694

A series of four S-allyl D-thiopyranosides, α- and β-manno and xylo, were oxidized with MCPBA at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was determined either directly by X-ray crystallography or by co

Full text of DOI:10.1021/ja0122694

Published on Web 05/07/2002
Stereoselective Formation of Glycosyl Sulfoxides and Their
Subsequent Equilibration: Ring Inversion of an
r-Xylopyranosyl Sulfoxide Dependent on the Configuration at
Sulfur
David Crich,*,† Jan Mataka,† Lev N. Zakharov,‡ Arnold L. Rheingold,‡ and
Donald J. Wink†
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061, and Department of Chemistry and
Biochemistry, UniVersity of Delaware, Academy Street, Newark, Delaware 19716
Received October 1, 2001
Abstract: A series of four S-allyl D-thiopyranosides, R- and â-manno and xylo, were oxidized with MCPBA
at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was
determined either directly by X-ray crystallography or by correlation with closely related structures. For the
axial thioglycosides oxidation leads very predominantly to the (R)S-diastereomer in the xylo series and
exclusively so in the manno series; the configuration at C2 is of little importance in determining the
stereoselectivity of oxidation of axial thioglycopyranosides. In the equatorial series the configuration at C2
has a significant effect on the outcome of the reaction as, although both series favored the (S)S-sulfoxide,
selectivity was significantly higher in the case of the â-mannoside than of the â-xyloside. The two R-xylo
sulfoxides have different conformations of the pyranoside ring with the (R)S-isomer adopting the 1C4 chair
4
and the (S)S-diastereomer the C1. Each pair of diastereomeric sulfoxides was thermally equilibrated in
C6D6 and in CD3OD. In the mannose series the kinetic isomers are also thermodynamically preferred. In
the xylose series, on the other hand, the nature of the thermodynamic isomer in both the R- and â-anomers
is a function of solvent with a switch observed on going from C6D6 to CD3OD. The results are rationalized
in terms of the exo-anomeric effect, steric shielding provided by H3 and H5 in the axial series, the interaction
of the C2-O2 and sulfoxide dipoles, and increased steric interactions on hydrogen bonding of the sulfoxides
to CD3OD.
of nucleosides.9,10 In the course of studies in this laboratory on
Introduction
the application of Kahne’s method in the mannose series,11,12
we made the unexpected observation that oxidation of an S-ethyl
4,6-O-benzylidene-protected R-mannothiopyranoside to the cor-
responding sulfoxide was highly stereoselective, giving, within
the limits of detection, a single diastereomer.13,14 The oxidation
of equatorial thioglycosides, on the other hand is typically rather
unselective and gives mixtures of both sulfoxides. Interestingly,
equatorial thioglycosides have been converted to glycosyl
sulfimides, by reaction with chloramine T, with excellent but
as yet undetermined diastereoselectivity.15,16
Since its introduction in 1989,1 Kahne’s sulfoxide glycosy-
lation method has been shown to be one of the more powerful
techniques available for the formation of glycosidic bonds. It
enables coupling to a wide range of carbohydrates, including
extremely complex and sensitive substrates2-5 and does so under
a standardized set of conditions.6 The method has also been
applied to solid-phase glycosylation, thereby enabling the
preparation of oligosaccharide libraries.7,8 The use of pyrimidine
bases as nucleophiles in this chemistry permits the formation
* To whom correspondence should be addressed. E-mail: dcrich@uic.edu.
† University of Illinois at Chicago.
Since the original observation that the axial thioglycoside 1
was converted with MCPBA to a single sulfoxide,13 we have
‡ University of Delaware.
(1) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc. 1989,
111, 6881-6882.
(2) Ge, M.; Thompson, C.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 11014-
(9) Chanteloup, L.; Beau, J.-M. Tetrahedron Lett. 1992, 33, 5347-5350.
(10) Crich, D.; Hao, X. J. Org. Chem. 1999, 64, 4016-4024.
(11) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(12) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(13) Crich, D.; Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605-615.
(14) The highly stereoselective oxidation of S-phenyl 3,4,6-tri-O-benzyl-R-D-
thiomannopyranoside and of S-ethyl R-D-thioglucopyranoside was also
reported, but the configuration at sulfur was not assigned. Stork, G.; La
Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248; Micheel, F.; Schmitz,
H. Ber. Deutsch. Chem. Ges. 1939, 72, 992.
(15) Cassel, S.; Plessis, I.; Wessel, H. P.; Rollin, P. Tetrahedron Lett. 1998, 39,
8097-8100.
(16) Chery, F.; Cassel, S.; Wessel, H. P.; Rollin, P. Eur. J. Org. Chem. 2002,
171-180.
11015.
(3) Gildersleeve, J.; Smith, A.; Sakurai, D.; Raghavan, S.; Kahne, D. J. Am.
Chem. Soc. 1999, 121, 6176-6182.
(4) Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999, 121, 1237-
1244.
(5) Nicolaou, K. C.; Mitchell, H. J.; Rodriguez, R. M.; Fylaktakidou, K. C.;
Suzuki, H.; Conley, S. R. Chem. Eur. J. 2000, 6, 3149-3165.
(6) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.
(7) Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994,
116, 6953-6954.
(8) Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan,
N.; Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.;
Kahne, D. Science 1996, 274, 1520-1522.
9
6028
J. AM. CHEM. SOC. 2002, 124, 6028-6036
10.1021/ja0122694 CCC: $22.00 © 2002 American Chemical Society

Stereoselective Formation of Glycosyl Sulfoxides
A R T I C L E S
Figure 1. Crystallographically determined configuration and conformation
of sulfoxides 2 and 3.
repeatedly observed that 4,6-O-benzylidene-protected axial
thioglycosides are transformed by a range of common oxidizing
agents with very high diastereoselectivity.12,17-20 X-ray crystal-
lographic analysis permitted the assignment of configuration
as (R)S in sulfoxide 2 and in the related 3.21 Benzylation of
sulfoxide 2 provided 4, which was also obtained selectively by
oxidation of the thioglycoside, and thus a third established
example of the (R)S configuration at which point we considered
the paradigm established and relented from our investigations
of configuration.21,22 The X-ray structures of 2 and 3 showed a
common conformation about the C1-S(-O)R bond with the
R group having a gauche relationship to the ring oxygen and
the S-O and C1-O5 dipoles aligned antiparallel, as depicted
in Figure 1. This in turn led us to postulate that the selectivity
is a result of the exo-anomeric effect, which with an axial
thioglycoside exposes the pro-R lone pair to solvent while
shielding the pro-S one under the pyranose ring.21 With
equatorial thioglycosides both lone pairs are exposed and
therefore mixtures of sulfoxides are obtained.
The axial (S)S-isomer of the above (R)S-sulfoxides is of
interest for a number of reasons but especially because it may
have interesting conformational effects on any pyranose system
into which it is built. As we have noted above, the (R)S-sulfoxide
retains the gauche conformation of the exo-anomeric effect and
opposes the S-O and C1-O5 dipoles. This conformation is
best seen in the Newman projection (Figure 1). In the (S)S-
diastereomer none of the three staggered conformations (10-
12) about the C1-S bond retains both of these favorable
attributes. If the dipoles are antiparallel (10), then the aglycon
suffers from an uncomfortably close 1,3-diaxial interaction with
H3 and H5 of the pyranose ring; if (11) the exo-anomeric
preferred conformation is retained, then it is the sulfoxide
oxygen that suffers from the 1,3-diaxial interaction. When 1,3-
diaxial interactions are avoided (12), there is a gauche relation-
ship between the two dipoles. A knowledge of sulfoxide
stereochemistry and conformation is also of considerable interest
in the light of Vasella’s lateral protonation model for glycosidase
enzymes,23,24 with the obvious implication being that the (R)S-
diastereomer should be the more active of the two in any
sulfoxide-based inhibitor.
The high selectivity on oxidation is neither restricted to the
mannose series, to pyranose rings, nor to 4,6-O-alkylidene-
protected systems. Similarly high selectivity was observed with
R-glucopyranosyl thioglycosides (e.g. 5)20 with a bicyclic
furanoside (6),10 and a bisacetal-protected system (7).19 An
especially interesting example is presented by the R-thioxyloside
8, whose predominant conformation is the 4C1 chair. On
oxidation with MCPBA one very predominant sulfoxide was
In this contribution we follow up on our earlier report of
stereoselective thioglycoside oxidation with an investigation into
the thermodynamic properties of eight sulfoxides as well as the
kinetically selective reactions by which they are obtained. In
undertaking the present investigation into the thermodynamic
and conformational aspects of glycosyl sulfoxides we faced two
primary problems. The first and most obvious of these was the
need for a method to assign sulfoxide configuration. Although
NMR methods for the assignment of sulfoxide configuration
in glycosyl sulfoxides25,26 are available, we have relied here on
a combination of X-ray crystallography and of extrapolation
1
obtained but as the C4 chair (9) as is evident from inspection
of the 1H NMR data.17,18 We did not assign configuration
rigorously in these latter cases but drew on an analogy with the
above crystallographically established examples.
(17) Crich, D.; Dai, Z. Tetrahedron 1999, 55, 1569-1580.
(18) Crich, D.; Dai, Z.; Gastaldi, S. J. Org. Chem. 1999, 64, 5224-5229.
(19) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(20) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926-4930.
(23) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750-
770.
(24) Varrot, A.; Schullein, M.; Pipelier, M.; Vasella, A.; Davies, G. J. J. Am.
Chem. Soc. 1999, 121, 2621-2622.
(25) Buist, P. H.; Behrouzian, B.; MacIsaac, K. D.; Cassel, S.; Rollin, P.; Imberty,
A.; Gautier, C.; Perez, S.; Genix, P. Tetrahedron: Asymmetry 1999, 10,
2881-2889. In this method the configuration at sulfur is deduced from
the direction of very small chemical shift changes in the sulfoxide on
introduction of (S)-R-methoxyphenylacetic acid. It has not yet been applied
to axial glycosyl sulfoxides.
(26) Khiar, N. Tetrahedron Lett. 2000, 41, 9059-9063. This empirical method
relies on the chemical shift difference between the two diastereotopic
methylene hydrogens in ethyl (and presumably other alkyl) glycosyl
sulfoxides. We have found several exceptions to this rule and therefore
recommend that it should only be applied with considerable caution.
(21) Crich, D.; Mataka, J.; Sun, S.; Lam, K.-C.; Rheingold, A. R.; Wink, D. J.
J. Chem. Soc., Chem. Commun. 1998, 2763-2764.
(22) One apparent exception to the above series of highly selective oxidations
is that of a fucopyranosyl thioglycoside, which was depicted as axial and
gave two diastereomeric sulfoxides. We believe this to be a drawing error
as the experimental part refers to the oxidation of a â-L-, and therefore
equatorial, fucopyranoside; a fact with which the NMR data concur.6
A
second apparent exception, that of the low-temperature MCPBA oxidation
of S-phenyl 2-O-TBDMS-4,6-O-benzylidene-3-O-p-methoxybenzyl- R-D-
thiomannoside, a very close analogue of 2, which was reported5 to give
two diastereoisomers, gave only one diastereoisomer in our hands. It is
perhaps relevant to note that minor amounts of sulfone are often formed
and that these are frequently surprisingly polar and therefore easily mistaken
for a second sulfoxide.
9
J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002 6029

A R T I C L E S
Crich et al.
reaction times gave a higher proportion of the kinetic â-isomer,
whereas prolonged exposure to the reaction conditions resulted
in an enhancement of the thermodynamically more stable
R-anomer. Both anomers existed in the 4C1 chair conformation,
as was the case with the corresponding S-phenyl thioxylosides,
3
although it is noteworthy from the reduced JH,H couplings
(Table 1) that another conformation, presumably the 1C4 chair,
is populated to a significant extent in 16. Oxidation of the
â-anomer 16 with MCPBA gave a 2.5/1 mixture) of sulfoxides
(18) and (19), consistent with the oxidation of the â-S-phenyl
system and of the Martin-Lomas â-S-phenyl thiogalactoside.
Accordingly, the major diastereomer (18) was assigned the (S)S
configuration. Both 18 and 19 are predominantly 4C1 chairs but,
again, it is apparent from analysis of the coupling constants
(Table 1) that another conformation is populated to some extent,
especially in 18.
Figure 2. X-ray crystallographic structure of sulfoxide 14.
from closely related molecules whose configuration was deter-
mined crystallographically. The second problem was one of how
to achieve equilibration of the glycosyl sulfoxides. Photolytic
equilibration, likely via radical pairs, was considered but found
to be impractical owing to the preponderance of degradation
products.27,28 Eventually, the allyl sulfoxide/sulfenate equili-
brium29-31 was found to be satisfactory and reduced the problem
to the relatively minor one of the synthesis of S-allyl thiogly-
cosides and their oxidation.
Synthesis, Assignment of Configuration, and Kinetic
Selectivity. As previously reported17 oxidation of S-phenyl 2,3,4-
tri-O-benzoyl-1-thio-â-D-xylopyranoside (13) with MCPBA at
-78 °C in dichloromethane gave a 3/1 mixture of diastereomeric
sulfoxides (14) and (15) which could be separated chromato-
graphically. After recrystallization from ethanol the major isomer
(14) was examined crystallographically, resulting in the assign-
ment of configuration at sulfur as (S)S (Figure 2). This
assignment, and the related observation by Martin-Lomas
wherein oxidation of a â-S-phenyl thiogalactoside also gave the
crystallographically determined (S)S-sulfoxide as the major
diastereomer32 suggests that the sense, if not the degree of
diastereoselectivity, is general for equatorial thioglycosides.33
Oxidation of the R-S-allyl xylopyranoside (17) is considerably
more interesting as, similar to its S-phenyl congenor (8), high
selectivity for one diastereomer was observed, along with a
complete change in conformation to the 1C4 inverted chair. This
substance (20) was assigned crystallographically as the (R)S-
sulfoxide (Figure 3), with the X-ray structure also revealing the
ring conformation. The change in conformation on formation
of the sulfoxide 20 holds in solution as well as in the crystal
and is readily apparent from the magnitude of the 3JH,H couplings
and from the 4JH3,H5eq w-coupling manifested by this sulfoxide
(Table 1). The adoption of the 1C4 conformation in peresterified
â-xylopyranosyl glycosides and halides, leading to the placement
of the electronegative group in the axial position where it
benefits from the anomeric effect, is a common phenomenon.34,35
A mixture of â-S-allyl 2,3,4-tri-O-benzoyl-1-thio-D-xylopy-
ranosides (16) and the R-anomer (17) was synthesized by action
of allyl mercaptan on tetrabenzoyl xylopyranose in the presence
of BF3 etherate and separated chromatographically. Shorter
1
The adoption of the C4 chair conformation by R-xylopyrano-
sides, thereby placing the anomeric substituent in an equatorial
position, is less common and was first seen with positively
charged anomeric substituents.34,36,37 The possibility that the
(27) Mislow, K.; Axelrod, M.; Rayner, D. R.; Gotthardt, H.; Coyne, L. M.;
Hammond, G. S. J. Am. Chem. Soc. 1965, 87, 4958-4959.
(28) Guo, Y.; Jenks, W. S. J. Org. Chem. 1997, 62, 857-864.
(29) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4869-4876.
(30) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-155.
(31) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120,
5961-5969.
(32) Khiar, N.; Alonso, I.; Rodriguez, N.; Fernandez-Mayorales, A.; Jimenez-
Barbero, J.; Nieto, O.; Cano, F.; Foces-Foces, C.; Martin-Lomas, M.
Tetrahedron Lett. 1997, 38, 8267-8270.
(33) The X-ray crystal structure of the (R)S-sulfoxide of S-ethyl 4,6-O-
benzylidene-2,3-di-O-acetyl-â-D-thioglucopyranoside has been published,
but the paper does not indicate whether it was the major or the minor
product of a relatively unselective (56:43) MCPBA oxidation of the
thioglyoside.25 A subsequent paper26 seems to suggest it is the minor product
which would conform with the oxidation of the S-phenyl â-thiogalactoside32
of Martin-Lomas and the S-phenyl â-xyloside presented here.
1
minor C4 conformer of the thioglycoside 17 was undergoing
oxidation more rapidly than the major 4C1 conformer was
considered improbable as this would entail oxidation of an
equatorial thioglycoside and thus would be predicted to be
considerably less stereoselective. Rather, it appeared likely that
(34) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen; Springer-Verlag: Berlin, 1983.
(35) For a detailed discussion of the conformation of “tetraaxial” â-xylopyra-
nosides see Lichtenthaler, F. W.; Lindner, H. J. Carbohydr. Res. 1990,
200, 91-99.
(36) Vaino, A. R.; Chan, S. S. C.; Szarek, W. A.; Thatcher, G. R. J. J. Org.
Chem. 1996, 61, 4514-4515.
(37) Vaino, A. R.; Szarek, W. A. J. Org. Chem. 2001, 66, 1097-1102.
9
6030 J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002

Stereoselective Formation of Glycosyl Sulfoxides
A R T I C L E S
Table 1. Chemical Shifts and Coupling Constantsa for the Xylopyranosides 16-21b
δH1
δH2
δH3
δH4
δH5eq
δH5ax
J1,2
J2,3
J3,4
J4,5ax
J4,5eq
J5a,5b
others
16
17
18
19
20
21
4.99
5.70
4.83
4.52
4.84
4.84
5.42
5.44
5.13
5.89
5.61
5.73
5.75
6.03
5.88
5.99
5.20
6.48
5.26-5.32
5.33-5.41
5.33-5.38
5.42-5.51
5.88
4.61
4.11
4.52
4.73
4.15
4.33
3.73
4.27
3.90
3.76-3.85
4.38
4.83
6.3
4.8
6.3
8.4
2.1
5.7
6.3
9.3
6.3
8.4
<2.0
8.4
6.9
9.3
6.3
8.4
<2.0
8.1
6.0
10.8
4.2
4.2
5.4
6.0
4.8
<2.0
4.8
12.3
10.8
12.6
11.4
13.2
11.4
n.d.c
<2.0
8.4
4J3,5eq 2.1
5.40-5.49
a All coupling constants in Hertz. b All data for CDCl3 solutions at ambient temperature. c n.d. ) not determined due to poor resolution.
oxidation with tert-butyl hypochlorite in methanol/dichlo-
romethane at -40 °C, according to Johnson,38 is significantly
less selective and provides a ratio of 2/1 of the (R)S/(S)S-isomers
4 and 28 from 29. This change in selectivity obviously results
from the different mechanism which does not involve direct
oxygen transfer to the sulfide but, rather, chlorination followed
by nucleophilic displacement. Unfortunately, even this method
failed with the S-allyl thioglycosides, owing to the rapid cleavage
of the allyl thioglycoside under the reaction conditions. A small
amount of the (S)S-diastereomer (27), sufficient for NMR
purposes, was eventually obtained from the equilibration studies
(vide infra).
The â-anomer (30), of 25, was best obtained39 by the triflic
anhydride-mediated coupling of the R-S-ethyl sulfoxide 4 with
Figure 3. X-ray crystallographic structure of sulfoxide 20.
freshly distilled allyl mercaptan.40 Low-temperature oxidation
Scheme 1
of 30 with MCPBA provided a 7/1 mixture of two sulfoxides
31 and 32, which could be separated by chromatography over
silica gel. The major isomer (31) was assigned the S-configu-
ration by analogy with that of the major diastereomer in the
â-thioxyloside and â-thiogalactoside series, both of which are
supported by crystallographic evidence (vide supra). Assuming
that the equatorial thioglycosides are oxidized from the ground-
state conformation about the glycosidic bond, namely that
imposed by the exo-anomeric effect, then the reasons underlying
the greater selectivity in the â-manno series than in the xylo
series are obvious. The pro-R lone pair is shielded to a
it was the major 4C1 conformer that was being oxidized
stereoselectively to the (R)S-isomer, according to the model
significantly greater extent in the manno series by the axial
substituent at C2.
previously advanced for axial thioglycosides, followed by an
inversion of conformation to accommodate the greater steric
requirements of the sulfoxide group. The minor isomer (21)
4
interestingly has the normal C1 chair conformation.
In the mannopyranose series an R-S-allyl thioglycoside (22)
was readily obtained by treatment of penta-O-acetyl mannopy-
ranose with allyl mercaptan and BF3. This could then be
converted to the 4,6-O-benzylidene-protected derivative 25 by
a standard set of reactions (Scheme 1). Oxidation of 25 with
MCPBA in dichloromethane at -78 °C was completely selec-
tive, affording a single diastereomeric sulfoxide (26) to which
we assign the (R)S configuration in accordance with the previous
crystallographic studies. Owing to the high kinetic selectivity
in the oxidation of the R-thiomannosides the isolation of
significant quantities of the minor diastereoisomer was prob-
lematic. As noted previously, in the S-ethyl series several
oxidants (mcpba, Oxone, MMPP, NaIO4) were all extremely
selective for the (R)S-isomer. Subsequently, we have found that
Thermodynamic Stereoselectivity. Both diastereomeric sul-
foxides in the R- and â-xylo and â-manno- series were subjected
(38) Johnson, C. R.; McCants, D. J. Am. Chem. Soc. 1965, 87, 1109-1114.
(39) Crich, D.; Li, H. J. Org. Chem. 2000, 56, 801-805.
(40) The â-selective S-alkylation of 1-deoxy-1-thio mannopyranose derivatives
was not satisfactory owing to difficulties in obtaining the requisite
â-thiopyranose. Haque, M. B.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc.,
Perkin Trans. 1 1998, 2881-2889.
9
J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002 6031

A R T I C L E S
Crich et al.
Table 2. Kinetic and Thermodynamic Ratiosa
Scheme 2
kinetic
(R)S/(S)S
thermodynamic
(R)S/(S)S
thermodynamic
(R)S/(S)S
(mcpba, CH Cl2,
(CD OD,
60 °C)
(C D ,
60 °C)
2
3
6 6
−78 0C)
19/18
20/21
32/31
26/27
â-xylo
0.4/1
1/0.1
0.2/1
1/0
1.5/1
2.5/1
n.d.b
2.6/1
0.7/1
0.5/1
0.04/1
3.1/1
R-xylo
â-manno
R-manno
oxidation, whereas the pro-S lone pair is shielded under the ring.
Any oxidation of the pro-S lone pair must bring the oxidant
into a significant steric clash with H’s 3 and 5 of the pyranose
ring or result from a higher-energy conformation about the
glycosidic bond. In a molecular orbital model of the exo-
anomeric effect oxidation would occur on the more exposed
lobe of the sulfur np-orbital.41 A similar analysis of the
â-thioglycosides is possible. Scheme 2 depicts an equatorial
thioglycoside with the exo-anomeric effect conformation; both
lone pairs are exposed, albeit to different degrees. Oxidation of
the pro-R lone pair requires approach of the oxidant past the
axial substituent at C2 and past the axial lone pair on the ring
oxygen and is apparently less favored than attack on the pro-S
lone pair which requires the oxidant to skirt the equatorial C2
substituent. In all established cases, it is the (S)S-sulfoxide that
is formed preferentially in the â-thioglycosides, even when the
large group at C2 is equatorial as in the xylosides. One possible
explanation for the favored formation of the (S)S-sulfoxides in
the â-xylo and related series, with the apparent preference for
approach of the oxidant along the more hindered trajectory,
invokes a destabilizing interaction between the axial lone pair
on the ring oxygen and the incoming oxidant in the formation
of the (R)S-sulfoxide. Alternatively, it may be that the oxidation
is best viewed in terms of the molecular orbital view of the
exo-anomeric effect in which the more exposed lobe of the
higher lying sulfur np-orbital undergoes electrophilic attack by
the oxidant. In the â-manno series the substituent at C2 is axial
and further hinders approach on the pro-R lone pair, leading to
the enhanced selectivity for the (S)S-sulfoxide over and above
that seen here in the â-xylo series and previously with
â-galactosides.32,33
The thermodynamics may be understood in terms of a
combination of steric effects and dipolar repulsions between
the S-O dipole on one hand and the endocyclic C1-O5 and
exocyclic C2-O2 dipoles on the other. In C6D6 in the equatorial
series (Scheme 2) the thermodymanically more stable (S)S-
sulfoxides can align the sulfoxide and endocyclic C-O dipoles
antiparallel. In this manner the R group of the sulfoxide occupies
the same space that it does in the exo-anomeric effect controlled
thioglycoside. In the â-xylo series studied this conformation,
and hence this configuration, is destabilized to some extent by
the parallel nature of the sulfoxide and exocyclic, equatorial
C2-O2 dipole which results in a relatively low thermodynamic
selectivity in the xylo series. In the X-ray structures of the (S)S-
sulfoxides of the â-xyloside 14 (Figure 2), and in a computed
structure of a related (S)S-â-glucosyl sulfoxide,25 this unfavor-
able dipolar interaction is relieved by adoption of a partially
eclipsed glycosidic bond.42 In the â-manno series, with the axial
C2-O2 bond, this unfavorable interaction is not present,
and the (S)S-sulfoxide is more strongly favored. We anticipate
that any eventual X-ray structures of (S)S-â-mannosyl or â-
a Determined by 1H NMR integration of crude reaction mixtures. b n.d.
) not determined.
to thermal equilibration in deuteriobenzene and deuteriomethanol
at 60 °C (Table 2). In the R-manno series, owing to the very
high kinetic selectivity, the minor diastereomer had first to be
obtained from equilibration of the major isomer before it could
be resubjected to the isomerization conditions. As expected from
the mechanism of these sulfoxide isomerizations,29 involving
the reversible allyl sulfoxide sulfenate rearrangement with a
reduction of polarity at the transition state, the equilibrations
were more rapid in C6D6 than in CD3OD. It is interesting to
note in passing that no glycosylation occurred on equilibration
in CD3OD, suggesting that the S-glycosyl O-allyl sulfenate ester
intermediates do not act as glycosyl donors unlike the related,
regioisomeric O-glycosyl S-phenyl sulfenates reported by the
Kahne group.31 This might be due to an innate lower reactivity
or may simply reflect their short lifetimes in an equilibrium
that strongly favors the sulfoxide form.
In deuteriobenzene in all cases but one the thermodynamic
and kinetically preferred products in a given system were the
same. Thus, oxidation of the â-xylopyranoside 16 gave a mixture
of 18 and 19 enriched in 18, either of which could be
equilibrated to a similar mixture favoring 18. Similarly in the
â-manno series, oxidation of 30 gave preferentially 31 over 32,
and equilibration also resulted in a significant preference for
31. In the R-manno series oxidation is extremely selective for
the formation of 26, equilibration of which provided a 10/1
mixture still favoring 26 over 27. In C6D6, therefore, it is only
in the R-xylo series that the kinetic and thermodynamic
sulfoxides differ in configuration with the oxidation of 17
affording very preferentially 20, whereas equilibration strongly
favors 21.
In deuteriomethanol however the pattern was different. As
in C6D6 equilibration of the R-mannosides in CD3OD strongly
favored the kinetic (R)S-isomer 27. No equilibration of the
â-manno series was conducted in CD3OD because of the small
amounts of material available. In CD3OD in the â-xylo series,
it is the (R)S-isomer 19 that is favored under equilibrating
conditions. In the R-xylo series the (R)S-isomer (20), with its
1C4 conformation, is the more stable sulfoxide in CD3OD
solution. Thus, in CD3OD the situation was the exact reverse
of that in C6D6 for both the R- and â-xylo series, whereas it
was unchanged for the R-mannosyl sulfoxides.
Discussion
The kinetic selectivities are best rationalized by consideration
of the exo-anomeric effect and the influence of the substituent
at C2 on the carbohydrate ring. As originally proposed for the
R-mannose series,21 the exo-anomeric effect imposes the
conformation depicted in Figure 1 on axial thioglycosides. This
results in the pro-R lone pair being exposed and available for
(41) For a detailed discussion of the pros and cons of the MO picture of the
anomeric and exo-anomeric effects see: Juaristi, E.; Cuevas, G. The
Anomeric Effect; CRC: Boca Raton, 1995.
9
6032 J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002

Stereoselective Formation of Glycosyl Sulfoxides
A R T I C L E S
Scheme 3
are augmented in CD3OD to the extent that the (R)S-isomer 20
with its 1C4 conformation and equatorial sulfoxide is now
favored. In the equatorial series the (S)S-sulfoxide is favored in
C6D6 but the (R)S-isomer in CD3OD. Again we attribute this
switch-over to the magnification of steric interactions arising
from hydrogen bonding of the sulfoxide to the solvent. As noted
above, the ideal conformation of the (S)S-â-xylo-sulfoxide (18)
with the antiparallel S-O and C1-O5 dipoles is destablized to
some extent by the interaction of the sulfoxide dipole with the
equatorial substituent at C-2 (Scheme 2) as reflected in the
crystal structure of 14 (Figure 2). When the sulfoxide is
hydrogen-bonded to the solvent, this interaction takes on a steric
as well as a dipolar component, and the combination is sufficient
to shift the equilibrium in favor of the (R)S-isomer (19). For
the R-mannosides the (R)S-isomer is favored under equilibrating
conditions in both C6D6 and CD3OD as this isomer is best able
to minimize dipolar and steric interactions. Although the
â-mannosides were not investigated in CD3OD, we expect that
the (S)S-isomer will be favored as in benzene as this isomer,
with its close parallels to the 1C4 (R)S-R-xyloside, best accom-
modates all dipolar and steric interactions.
The final question is simply why is 21 more stable in C6D6
than 20eq with its favored sulfoxide conformation and config-
uration? The answer must quite simply be that 21 benefits from
both the anomeric effect and the equatorial disposition of its
other three substituents and that these two effects combined
outweigh any advantages present in the favored conformation
about the glycosidic bond in 20eq. This small advantage is easily
overridden in CD3OD when increased 1,3-diaxial interactions
arising from solvation of the sulfoxide cause a shift in favor of
20eq.
rhamnosyl sulfoxides will exhibit the fully staggered conforma-
tion depicted in Scheme 2.
In the R-manno series the S-O and endocyclic dipoles are
almost perfectly antiparallel which results in the R group
occupying the space it would in a typical exo-anomeric effect
conformation (Figure 1) as demonstrated crystallographically
with the S-ethyl sulfoxides 2 and 3.
In C6D6 solution the R-xylo series is the anomaly. It conforms
to the usual rule for selective formation of the (R)S-sulfoxide
under kinetic conditions, but the (S)S-diastereomer is preferred
on equilibration. Moreover, the kinetic isomer 20 adopts the
inverted 1C4 chair conformation. It is readily appreciated
4
(Scheme 3) that in the C1 conformation of the kinetic isomer
(20ax) with the sulfoxide and endocyclic C1-O5 dipoles
antiparallel, the sulfoxide and exocyclic C2-O2 dipoles are
aligned and repel each other. The kinetic isomer therefore prefers
1
the inverted C4 conformation with the equatorial sulfoxide
(20eq). In this inverted conformation the sulfoxide dipole sets
itself antiparallel to the endocyclic C-O dipole and thus is not
in conflict with the exocyclic C2-O2 dipole (Figure 3), that
is, the situation is identical to that of the strongly favored (S)S-
sulfoxide (31) in the â-manno series.43 In C6D6 solution the
thermodynamically more stable (S)S-R-sulfoxide retains the 4C1
chair conformation 21 for which all of the staggered conforma-
tions about the glycosidic bond, 10, 11 and 12, are disfavored
to some extent. We suggest that it approximates to an eclipsed
conformation akin to 33 which minimizes dipolar repulsions
and avoids any strong steric interactions with H3 and H5. A
conformation of this type is especially envisaged because of
the very downfield shift of H3 (δ 6.48) which indicates that
H3 is exposed to the deshielding environment of the positive
sulfur center rather than to a lone pair or sulfoxide oxygen.
Sulfoxide 21 presumably does not undergo the ring flip as its
1C4 sulfoxide would not benefit from the special circumstances
of its isomer 20eq, that is, it would be equivalent to the strongly
disfavored â-manno sulfoxide 32.
Experimental Section
General. Unless otherwise stated H and 13C NMR spectra were
1
recorded as CDCl3 solutions at 300 and 75 MHz, respectively, with
chemical shifts in ppm downfield from tetramethylsilane. Specific
rotations are for CHCl3 solutions. IR spectra were recorded as casts on
NaCl plates. Commercial MCPBA was purified by extraction.44 All
solvents were dried and distilled by standard means. FAB and ESI
HRMS were conducted by the University of Minnesota mass spec-
troscopy laboratory and the UIC Research Resources Center, respec-
tively. Microanalyses were carried out by Midwest Microlabs, India-
napolis.
S-Ethyl 4,6-O-Benzylidene-1-thio-r-D-mannopyranoside (R)S-
Oxide (2). S-Ethyl 4,6-O-benzylidene-1-thio-R-D-mannopyranoside
(0.281 g, 0.90 mmol) was dissolved in CH2Cl2 (44 mL), and placed in
an ice/H2O bath. MCPBA (0.202 g, 1 equiv), dissolved in CH2Cl2 (4
mL), was added slowly dropwise, and the resulting solution left to stir
for 50 min at 0 °C. The reaction was quenched with saturated NaHCO3
(4 mL), and following separation of the organic and aqueous layers,
the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The pooled
organic phases were washed with brine (25 mL), dried (Na2SO4), and
concentrated under vacuum, leaving a white solid (0.274 g, 93%). Mp
Under equilibrating conditions in CD3OD additional steric
factors come into play arising from hydrogen bonding of the
sulfoxide group with the solvent. Thus, in the (S)S-R-xyloside
21, preferred in C6D6, the destabilizing 1,3-diaxial interactions
(42) Note that, if the exo-anomeric effect is the interaction of a lone pair of the
glycosidic sulfur (oxygen in a normal O-glycoside) with the σ* orbital of
the endocyclic C1-O5 bond, the effect per se does not exist in conforma-
tions such as that in Figure 1, formulas 10 and 12, and the major sulfoxide
of Scheme 2. It cannot be said, therefore, that in a partially eclipsed
conformation the exo-anomeric effect is disrupted for such sulfoxides.
(43) The inversion could be seen as a manifestation of the reverse anomeric
effect,34 but as this effect has been largely discredited36,37 this is seen as
unlikely.
1
190 °C; [R]D ) +62° (c ) 0.5, MeOH); H NMR δ 7.45-7.49 (m,
2H), 7.36-7.39 (m, 3H), 5.58 (s, 1H), 4.72 (s, 1H), 4.66 (d, J ) 3.0
Hz, 1H), 4.21-4.27 (m, 2H), 4.06-4.09 (m, 1H), 3.73-3.77 (m, 2H),
(44) Schwartz, N. N.; Blumbergs, J. H. J. Org. Chem. 1964, 29, 1976.
9
J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002 6033

A R T I C L E S
Crich et al.
2.96-3.01 (m, 1H), 2.71-2.78 (m, 1H), 2.20-2.80 (br s, 2H), 1.40 (t,
J ) 7.5 Hz, 3H); 13C NMR δ 136.9, 129.5, 129.1, 128.5, 126.4, 102.5,
93.2, 69.3, 68.6, 68.3, 67.1, 44.0, 6.0; IR 1041 cm-1; ESIHRMS Calcd
for C15H20O6NaS [M + Na]+: 351.0888, found: 351.0878.
(m, 5H), 7.32-7.57 (m, 10H), 5.99 (t, J ) 8.4 Hz, 1H), 5.89 (t, J )
8.4 Hz, 1H), 5.74-5.85 (m, 1H), 5.42-5.51 (m, 3H), 4.73 (dd, J )
11.4 and 4.8 Hz, 1H), 4.52 (d, J ) 8.4 Hz, 1H), 3.76-3.85 (m, 3H);
13C NMR δ 165.8, 165.5, 164.9, 133.7, 133.7, 133.6, 130.3, 130.0,
130.0, 130.0, 128.9, 129.0, 128.8, 128.8, 128.6, 128.6, 128.4, 125.7,
124.5, 87.1, 72.4, 69.3, 67.2, 67.0, 52.3; IR υ 1727, 1660, 1583, 1451,
1316, 1281, 1256, 1177, 1094, 1068, 1027, 707 cm-1; FABHRMS
Calcd for C29H26NaO8S (M + Na)+ 557.1246, found: 557.1259.
S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-r-D-xylopyranoside (R)S-Oxide
(20). MCPBA (100%, 18.7 mg, 0.108 mmol) in CH2Cl2 (1.0 mL) was
added dropwise at -78 °C to a stirred solution of 17 (58 mg, 0.107
mmol) in CH2Cl2 (1.5 mL). After stirring at -78 °C for 2 h, the reaction
mixture was allowed to warm to 0 °C and quenched with saturated
NaHCO3 (1 mL). The aqueous phase was extracted with CH2Cl2 (3 ×
10 mL), and the pooled organic layers were washed with brine, dried
(Na2SO4), and concentrated. The crude product was then purified by
S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-â-D-xylopyranoside (16). 1,2,3,4-
Tetra-O-benzoyl-â-D-xylopyranoside (1.026 g, 1.81 mmol) was dis-
solved in CH2Cl2 (6.0 mL) under argon. Freshly distilled allyl mercaptan
(225 µL, 3.53 mmol) was added, followed by the slow dropwise
addition of BF3‚OEt2 (300 µL, 2.4 mmol). The reaction mixture was
stirred for 1.5 h at 25 °C, after which it was quenched with saturated
NaHCO3 (3 mL). The resulting aqueous layer was extracted with CH2-
Cl2 (3 × 10 mL), and the pooled organic extracts were then washed
with brine (20 mL), dried (Na2SO4), and concentrated. Crystallization
from hexanes/EtOAc at 4 °C removed the majority of the minor
R-anomer, after which purification of the mother liquor on a silica gel
column (eluent: CHCl3) afforded 16 as an oil (0.299 g, 31%). [R]25
D
) -3.0 (c ) 1.0); 1H NMR δ 7.97-8.03 (m, 6H), 7.49-7.56 (m, 3H),
7.32-7.41 (m, 6H), 5.73-5.88 (m, 1H), 5.75 (t, J ) 6.9 Hz, 1H), 5.42
(t, J ) 6.3 Hz, 1H), 5.26-5.32 (m, 1H), 5.19 (d, J ) 17.1 Hz, 1H),
5.16 (d, J ) 10.0 Hz, 1H), 4.99 (d, J ) 6.3 Hz, 1H), 4.61 (dd, J )
12.3 and 4.2 Hz, 1H), 3.73 (dd, J ) 12.3 and 6.0 Hz, 1H), 3.40 (dd, J
) 13.5 and 8.4 Hz, 1H), 3.27 (dd, J ) 13.2 and 6.0 Hz, 1H); 13C
NMR δ 165.7, 165.4, 165.3, 133.6, 133.5, 133.5, 130.1, 130.0, 129.4,
129.1, 128.5, 128.5, 118.3, 81.4, 70.7, 70.3, 69.1, 63.6, 33.6; ESIHRMS
Calcd for C27H30NO7S (M + NH4)+: 536.1743, found: 536.1746.
S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-r-D-xylopyranoside (17). 1,2,3,4-
Tetra-O-benzoyl-â-D-xylopyranoside (0.600 g, 1.06 mmol) and allyl
mercaptan (0.20 mL, 8.5 mmol) were dissolved in CH2Cl2 (4.0 mL),
BF3‚OEt2 (0.13 mL, 1.06 mmol) was added dropwise, and the reaction
mixture was stirred under argon for 72 h. The reaction mixture was
diluted with saturated NaHCO3 (10 mL), and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The pooled organic phases were
washed with brine (15 mL) and then dried (MgSO4) and concentrated.
The isolated product was purified by repeated chromatography on silica
gel column (eluent: CHCl3/hexanes, 10/1) to afford pure 17 as a white
solid (84 mg, 16%), along with the â-anomer (16) (64 mg, 11%). Mp
162 °C; [R]25D ) 8.0 (c ) 2.0); 1H NMR δ 7.82-8.02 (m, 5H), 7.29-
7.56 (m, 10H), 6.03 (t, J ) 9.3 Hz, 1H), 5.67-5.81 (m, 1H), 5.70 (d,
J ) 4.8 Hz, 1H), 5.44 (dd, J ) 9.3 and 4.8 Hz, 1H), 5.33-5.41 (m,
1H), 5.10-5.19 (m, 2H), 4.27 (t, J ) 10.8 Hz, 1H), 4.11 (dd, J ) 10.8
and 5.4 Hz, 1H), 3.26 (dd, J ) 13.5 and 8.4 Hz, 1H), 3.16 (dd, J )
13.5 and 5.7 Hz, 1H); 13C NMR δ 165.7, 165.6, 165.5, 133.6, 133.5,
133.4, 133.1, 130.14, 130.0, 129.9, 129.9, 129.3, 129.2, 129.1, 128.6,
128.6, 128.5, 118.3, 81.3, 71.3, 70.2, 69.9, 60.2, 32.6. Anal. Calcd for
C29H26O7S: C, 66.61; H, 5.05. Found: C, 66.68; H, 5.13.
prep TLC (eluent: hexanes/EtOAc, 1/1) to give 20 (37.4 mg, 65%).
1
Mp 171-174 °C; [R]25 ) -82 (c ) 0.44); H NMR δ 8.19 (d, J )
D
8.4 Hz, 2H), 8.07 (dd, J ) 8.4 and 1.2 Hz, 2H), 7.80 (dd, J ) 8.4 and
0.9 Hz, 2H), 7.61-7.67 (m, 2H), 7.39-7.53 (m, 5H), 7.06 (t, J ) 8.1
Hz, 2H), 5.95-6.15 (m, 1H), 5.88 (m, 1H), 5.61 (br s, 1H), 5.55 (d, J
) 9.9 Hz, 1H), 5.48 (d, J ) 16.8 Hz, 1H), 5.20 (d, J ) 1.8 Hz, 1H),
4.84 (d, J ) 2.1 Hz, 1H), 4.38 (d, J ) 13.2 Hz, 1H), 4.15 (dd, J )
13.2 and 2.1 Hz, 1H), 3.84 (dd, J ) 13.8 and 6.9 Hz, 1H), 3.53 (dd, J
) 13.8 and 8.4 Hz, 1H); 13C NMR δ 165.5, 165.0, 164.1, 134.1, 133.7,
133.5, 130.4, 130.1, 130.0, 129.3, 129.0, 128.8, 128.7, 128.6, 128.3,
125.6, 124.2, 88.5, 67.5, 66.7, 66.1, 65.7, 52.9; FABHRMS Calcd for
C29H26NaO8S (M + Na)+: 557.1246, found: 557.1259.
S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-r-D-xylopyranoside (S)S-Oxide
(21). Sulfoxide 20 (6.0 mg) in C6D6 (0.5 mL) was heated to 60 °C in
an NMR tube with periodic monitoring by 1H NMR spectroscopy. After
3 days the contents were separated via prep TLC (eluent: hexanes/
EtOAc, 1/1) and then column chromatography on silica gel (eluent:
hexanes/EtOAc, 2/1) leading to the isolation of 21 (2.8 mg, 47%).
1H NMR δ 8.07 (d, J ) 9.0 Hz, 2H), 7.96 (d, J ) 8.7 Hz, 4H),
7.31-7.57 (m, 9H), 6.48 (t, J ) 8.4 Hz, 1H), 5.79-5.93 (m, 1H), 5.73
(dd, J ) 8.4 and 5.4 Hz, 1H), 5.45 (m, 1H), 5.42 (d, J ) 18.3 Hz, 1H),
5.39 (d, J ) 9.9 Hz, 1H), 4.80-4.87 (m, 2H), 4.33 (dd, J ) 11.1 and
4.8 Hz, 1H), 3.86 (dd, J ) 12.9 and 8.1 Hz, 1H), 3.75 (dd, J ) 12.6
and 7.2 Hz, 1H); 13C NMR δ 134.1, 133.6, 133.5, 130.4, 130.1, 130.0,
129.9, 129.0, 128.8, 128.6, 128.6, 125.7, 124.3, 85.6, 70.2, 69.3, 69.0,
66.7, 52.3; IR υ 1720, 1451, 1278, 1256, 1091, 1067, 1027, 699 cm-1
;
FABHRMS Calcd for C29H26NaO8S (M + Na)+: 557.1246; found:
557.1268.
S-Allyl 2,3,4,6-Tetra-O-acetyl-1-thio-r-D-mannopyranoside (22).
D-Mannose pentaacetate (4.07 g, 10.5 mmol) in CH2Cl2 (14.7 mL) was
stirred with allyl mercaptan (1.71 mL, 21.4 mmol) and BF3‚OEt2 (2.2
mL, 18.1 mmol) for 3 days at room temperature and then treated with
saturated NaHCO3, extracted with CH2Cl2 (3 × 50 mL), washed with
saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), and
concentrated. The resulting red oil was purified on a silica gel column
(eluent: hexanes/EtOAc, 2/1), yielding 22 as a white crystalline solid
(1.37 g, 32%). Mp 65-67 °C; [R]25D ) 67 (c ) 1.0); 1H NMR δ 5.70-
5.84 (m, 1H), 5.25-5.35 (m, 3H), 5.11-5.19 (m, 3H), 4.27-4.40 (m,
2H), 4.08 (dd, J ) 10.2 and 1.8 Hz, 1H), 3.11-3.26 (m, 2H), 2.15 (s,
3H), 2.09 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H); 13C NMR δ 170.7, 170.0,
169.9, 169.8, 132.6, 118.8, 80.9, 71.1, 69.8, 69.1, 66.4, 62.6, 33.3, 21.0,
20.9, 20.8, 20.8; ESIHRMS Calcd for C17H28NO9S (M + NH4)+:
422.1485, found: 422.1496.
S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-â-D-xylopyranoside (S)S-Oxide
(18) and S-Allyl 2,3,4-Tri-O-benzoyl-1-thio-â-D-xylopyranoside (R)S-
Oxide (19). MCPBA (100%, 0.0912 g, 0.53 mmol) in CH2Cl2 (0.85
mL) and added dropwise at -78 °C to a stirred solution of 16 (0.274
g, 0.53 mmol) in CH2Cl2 (6.7 mL). The reaction was left to stir for 2
h and then was gradually warmed to 2 °C and quenched with saturated
NaHCO3 (2 mL). The resulting aqueous layer was extracted with CH2-
Cl2 (3 × 5 mL), and after pooling, the organic extracts were washed
with brine (5 mL), dried (Na2SO4), and concentrated. Chromatography
on silica gel (eluent: CHCl3/EtOAc/hexanes, 3/1/1) gave 18 (213 mg,
75%) and 19 (67.3 mg, 24%). (18): mp 80-82 °C; [R]25 ) -43 (c
D
1
) 1.0); H NMR δ 7.95-8.03 (m, 5H), 7.31-7.43 (m, 10H), 5.96-
6.10 (m, 1H), 5.88 (t, J ) 6.3 Hz, 1H), 5.73 (t, J ) 6.3 Hz, 1H), 5.47-
5.67 (m, 2H), 5.33-5.38 (m, 1H), 4.83 (d, J ) 6.3 Hz, 1H), 4.52 (dd,
J ) 12.6 and 4.2 Hz, 1H), 3.90 (dd, J ) 12.6, 6.6 Hz, 1H), 3.80 (m,
1H), 3.68 (dd, J ) 13.5 and 4.2 Hz, 1H); 13C NMR δ 165.6, 165.4,
133.8, 133.8, 130.2, 130.1, 130.1 129.9, 128.7, 128.6, 125.6, 124.6,
90.1, 69.8, 68.0, 67.2, 65.7, 52.6; IR υ 1722, 1602, 1583, 1451, 1314,
1278, 1259, 1148, 1106, 1093, 1068, 1025, 708 cm-1; FABHRMS
Calcd for C29H26NaO8S (M + Na)+: 557.1246, found: 557.1255.
(19): mp 60-62 °C; [R]25D ) -4.9 (c ) 1.0); 1H NMR δ 7.80-7.92
S-Allyl 1-Thio-r-D-mannopyranoside (23). To a solution of 22
(1.209 g, 3.25 mmol) in distilled MeOH (11.7 mL) was added sodium
(0.073 g, 3.04 mmol), followed by stirring for 2 h. The pH of the
mixture was adjusted to neutrality with amberlyst 15 ion-exchange resin
and then dried (Na2SO4) and concentrated to yield 23 as a glass (0.536
1
g, 76%); [R]25 ) 19 (c ) 1.0); H NMR (CD3OD) δ 5.76-5.90 (m,
D
9
6034 J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002

Stereoselective Formation of Glycosyl Sulfoxides
A R T I C L E S
1H), 5.08-5.21 (m, 3H), 3.61-3.91 (m, 6H) 3.29 (dd, J ) 13.8 and
8.4 Hz, 1H), 3.15 (dd, J ) 13.5 and 5.1 Hz, 1H); 13C NMR (CD3OD)
δ 138.2, 118.0, 84.9, 75.2, 73.8, 73.6, 69.1, 62.9, 33.9; ESIHRMS Calcd
for C9H16NaO5S (M + Na)+: 259.0616, found: 259.0611.
S-Allyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-r-D-mannopy-
ranoside (S)S-Oxide (27). Equilibration of 26 (2.4 mg) in CD3OD for
three weeks at 60 °C gave a mixture of 26 and 27. Separation by
chromatography on silica gel (eluent: CHCl3/hexanes/methanol, 25/
1
9/1) gave 26 (0.6 mg, 25%) and 27 (0.3 mg, 12%). H NMR (500
S-Allyl 4,6-O-Benzylidene-1-thio-r-D-mannopyranoside (24). Ben-
zaldehyde dimethyl acetal (BDA) (172 µL 1.15 mmol) was added
dropwise at 0 °C to a stirred solution of 23 (0.271 g, 1.15 mmol) and
camphorsulfonic acid (CSA) (27 mg, 0.12 mmol) in freshly distilled
THF (5.4 mL). After stirring for 20 min at 0 °C and 20 min at room
temperature the reaction mixture was heated to reflux for 1 h and then
concentrated to remove MeOH, replenished with solvent, and concen-
trated again. The reaction was repeated with 23 (0.2036 g, 0.86 mmol),
BDA (129 µL, 0.86 mmol), and CSA (0.0211 g, 0.091 mmol). The
crude products from both preparations were combined and purified on
a silica gel column (eluent: hexanes/EtOAc, 2/1f1/3), to give 24 as
a white solid (0.307 g, 47%). Mp 150-153 °C; [R]25D ) 51 (c ) 1.5);
1H NMR δ 7.46-7.51 (m, 2H), 7.36-7.40 (m, 3H), 5.76-5.81 (m,
1H), 5.67 (s, 1H), 5.29 (s, 1H), 5.17 (d, J ) 17.4 Hz, 1H), 5.16 (d, J
) 9.3 Hz, 1H), 3.81-4.28 (m, 6H), 3.25 (dd, J ) 13.8 and 8.7 Hz,
1H), 3.15 (dd, J ) 13.8 and 3.1 Hz, 1H), 2.55-2.95 (br s, 2H); 13C
NMR δ 137.2, 133.1, 129.4, 128.5, 126.4, 118.4, 102.5, 83.2, 79.3,
72.4, 69.4, 68.8, 63.7, 33.2; ESIHRMS Calcd for C16H20NaO5S (M +
Na)+: 347.0929, found: 347.0919.
MHz) δ 7.10-7.54 (m, 15H), 5.71-5.77 (m, 1H), 5.62 (s, 1H), 5.31-
5.36 (m, 2H), 4.92-4.62 (m, 5H), 4.35-4.41 (m, 3H), 4.23 (dd, J )
4.5 and 1.2 Hz, 1H), 3.70-3.90 (m, 2H), 3.62 (m, 1H), 3.52-3.57
(dd, J ) 9.0 and 4.5 Hz, 1H); C NMR (125 MHz) δ 138.6, 137.9,
137.4, 129.0, 128.7, 128.5, 128.3, 128.2, 127.8, 126.3, 125.5, 124.4,
13
101.9, 88.8, 79.0, 78.7, 74.0, 73.3, 70.6, 68.7, 53.0.
S-Ethyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-r-D-mannopy-
ranoside (S)S-Oxide (28). tert-Butyl hypochlorite (24 µL)45 was added
in 4-µL amounts over a 2-h period at -78 ° to stirred solution of 2912
(0.110 g, 0.22 mmol) in CH2Cl2 (1.1 mL) and MeOH (1.1 mL) which
had been shielded from the light. The reaction mixture was then allowed
to warm to -20 °C, was quenched with 10% aqueous Na2CO3 (6 mL),
and diluted with CH2Cl2 (40 mL). The aqueous layer was extracted
with CH2Cl2 (4 × 20 mL), and then dried (MgSO4), and concentrated.
Chromatography on silica gel (eluent: hexanes/EtOAc, 2/1f1/1) gave
89.5 mg of a mixture enriched in 28 of which 32.1 mg was further
separated on a silica gel column (eluent: CHCl3/MeOH, 50/1) to give
1
the pure SS-isomer (3.8 mg, 3%). [R]25 ) 120 (c ) 0.1); H NMR
D
(400 MHz) δ 7.26-7.47 (m, 2H), 7.20-7.40 (m, 13 H), 5.62 (s, 1H),
4.90 (d, J ) 11.9 Hz, 1H), 4.84 (d, J ) 12.0 Hz, 1H), 4.69 (d, J )
11.9 Hz, 1H), 4.66 (d, J ) 12.0 Hz, 1H), 4.40-4.50 (m, 1H), 4.29-
4.37 (m, 4H), 4.15 (s, 1H), 3.75 (t, J ) 10.1 Hz, 1H), 2.76-2.82 (m,
1H), 2.64-2.68 (m, 1H), 1.24 (t, J ) 7.6 Hz, 3H); 13C NMR (100
MHz) δ 137.6, 129.2, 128.8, 128.6, 128.4, 128.2, 127.9, 126.4, 102.0,
90.1, 78.9, 76.6, 74.2, 70.5, 68.8, 42.6, 7.3; IR υ 1100, 1051, 1023,
970 cm-1; ESIHRMS Calcd for C29H32NaO6S (M + Na)+: 531.1817,
found: 531.1835.
S-Allyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-r-D-mannopy-
ranoside (25). Sodium hydride (0.0794 g, 1.82 mmol) was slowly added
portionwise at 0 °C to a solution of benzyl bromide (165 µL, 1.42
mmol) and thioglycoside 24 (0.145 g, 0.45 mmol) in THF (2.9 mL)
followed by stirring at room temperature for 4.5 h and then heating to
reflux for 5 h. The reaction mixture was concentrated and then
redissolved in EtOAc (20 mL), washed with water (10 mL) and brine
(10 mL), and dried (MgSO4). The crude product was concentrated and
purified on a silica gel column (eluent: hexanes/EtOAc, 10/1), to give
S-Allyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-â-D-mannopy-
ranoside (30). Triflic anhydride (38.5 µL, 0.24 mmol) was added
dropwise at -78 °C to a solution of 412 (0.102 g, 0.21 mmol) and
2,4,6 tri-tert-butyl pyrimidine46 (0.103 g, 0.42 mmol) in CH2Cl2 (3.0
mL). After stirring for 20 min freshly distilled allyl mercaptan (60 µL,
0.60 mmol) in CH2Cl2 (0.5 mL) was added dropwise followed by
stirring at -78 °C for 3 h. After warming up to -25 °C, the reaction
was quenched with saturated NaHCO3 (2 mL) and then further diluted
with saturated NaHCO3 (4 mL) and CH2Cl2 (30 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL), and the pooled organic
extracts were washed with water (20 mL) and brine (20 mL), dried
(MgSO4), and concentrated. Chromatography on silica gel column
1
25 as a clear oil (0.165 g, 73%). [R]25 ) 68 (c ) 0.5); H NMR δ
D
7.49-7.53 (m, 2H), 7.29-7.40 (m, 13H), 5.67-5.80 (m, 1H), 5.64 (s,
1H), 5.24 (d, J ) 0.9 Hz, 1H), 5.13 (d, J ) 16.2 Hz, 1H), 5.12 (d, J
) 10.8 Hz, 1H), 4.77 (d, J ) 12.0 Hz, 1H), 4.73 (s, 2H), 4.61 (d, J )
12.0 Hz, 1H), 4.12-4.32 (m, 3H), 3.86-3.93 (m, 3H), 3.20 (dd, J )
13.2 and 8.4 Hz, 1H), 3.09 (dd, J ) 13.8 and 6.0 Hz, 1H); 13C NMR
δ 138.5, 138.0, 137.8, 129.0, 128.6, 128.5, 128.3, 128.1, 128.0, 127.8,
127.7, 126.2, 126.1, 118.2, 101.6, 82.3, 79.4, 78.1, 76.7, 73.3, 73.2,
73.1, 68.8, 65.0, 33.5; FABHRMS Calcd for C30H33O5S (M + H)+:
505.2048; found: 505.2009.
S-Allyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-r-D-mannopy-
ranoside RS-Oxide (26). MCPBA (100%, 5.9 mg, 0.034 mmol) in CH2-
Cl2 (1.0 mL) and added dropwise at -78 °C to a stirred solution of
thioglycoside 25 (17.3 mg, 0.034 mmol) in CH2Cl2 (1.5 mL). After
stirring for 2 h, the reaction mixture was allowed to warm to -30 °C
and then quenched with saturated NaHCO3 (1 mL). CH2Cl2 (10 mL)
and saturated NaHCO3 (5 mL) were added to dilute the mixture, and
the aqueous phase was then extracted with CH2Cl2 (3 × 10 mL). The
organic extracts were pooled and washed with brine (15 mL), dried
(eluent: hexanes/EtOAc, 5/1) afforded 30 as an oil (37.2 mg, 35%).
1
[R]25 ) -33 (c ) 0.2); H NMR δ 7.29-7.53 (m, 15H), 5.74-5.88
D
(m, 1H), 5.64 (s, 1H), 5.12 (d, J ) 10.2 Hz, 1H), 5.10 (d, J ) 17.1 Hz,
1H), 5.03 (d, J ) 11.1 Hz, 1H), 4.87 (d, J ) 12.6 Hz, 1H), 4.82 (d, J
) 11.7 Hz, 1H), 4.73 (d, J ) 12.3 Hz, 1H), 4.58 (s, 1H), 4.30 (d, J )
9.9 Hz, 1H), 4.28 (dd, J ) 10.2 and 3.3 Hz, 1H), 4.00 (d, J ) 3.3 Hz,
1H), 3.83 (t, J ) 10.5 Hz, 1H), 3.78 (dd, J ) 9.9 and 3.3 Hz, 1H)
3.42-3.35 (m, 2H), 3.26 (dd, J ) 13.5 and 5.7 Hz, 1H); 13C NMR δ
138.6, 138.2, 137.7, 134.0, 129.0, 128.8, 128.5, 128.3, 127.8, 127.7,
126.2, 117.73, 101.6, 83.9, 80.1, 79.0, 78.5, 75.8, 73.2, 71.9, 68.6, 33.9;
FABHRMS Calcd C30H32O6S M+: 504.1970, found: 504.1950.
(Na2SO4), and concentrated, to give 26 as a glass (18.4 mg, 100%).
1
[R]25 ) -20 (c ) 0.1); H NMR δ 7.29-7.49 (m, 15H), 5.81-5.95
D
(m, 1H), 5.63 (s, 1H)), 5.49 (d, J ) 9.6 Hz, 1H), 5.40 (dd, J ) 17.1
and 1.2 Hz, 1H), 4.83 (d, J ) 11.7 Hz, 1H), 4.80 (d, J ) 11.7 Hz, 1H),
4.72 (d, J ) 1.2 Hz, 1H), 4.70 (d, J ) 11.7 Hz, 1H), 4.67 (d, J ) 12.0
Hz, 1H), 4.48 (dd, J ) 3.3 and 1.5 Hz, 1H), 4.34 (t, J ) 9.5 Hz, 1H),
4.20 (dd, J ) 9.6 and 4.2 Hz, 1H), 4.10 (dd, J ) 9.9 and 3.6 Hz, 1H),
3.80 (t, J ) 9.9 Hz, 1H), 3.73 (dd, J ) 8.7 and 3.9 Hz, 1H), 3.66 (dd,
J ) 10.2 and 6.6 Hz, 1H), 3.32 (dd, J ) 13.8 and 8.1 Hz, 1H); 13C
NMR δ 138.2, 137.7, 137.3, 129.2, 128.6, 128.5, 128.4, 128.1, 127.8,
126.1, 124.8, 124.6, 101.7, 91.9, 78.0, 77.6, 76.3, 74.2, 73.3, 73.1, 70.3,
S-Allyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-â-D-mannopy-
ranoside S-Oxide (S)S (31)- and (R)S (32)-Isomers. A solution of 30
(14.4 mg, 0.028 mmol) in CH2Cl2 (1.0 mL) was stirred at -78 °C and
titrated with MCPBA (100%, 5.6 mg, 0.033 mmol) in CH2Cl2 (1.0 mL)
until the reaction was judged to be complete by TLC (eluting solvent:
hexanes/EtOAc, 1/1). The reaction mixture was further stirred for 2 h
at -78 °C and then quenched at -69 °C with saturated NaHCO3 (1
68.3, 53.6; IR υ 1124, 1092, 1069, 1033, 1028, 1005, 993 cm-1
;
(45) Mintz, M. J.; Walling, C. Organic Syntheses; Wiley & Sons: New York,
1973; Collect. Vol. 5, pp 184-187.
(46) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-326.
ESIHRMS Calcd for C30H32NaO6S (M + Na)+: 543.1817, found:
543.1843.
9
J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002 6035

A R T I C L E S
Crich et al.
mL). The mixture was then diluted with CH2Cl2 (10 mL) and NaHCO3
(2 mL), and the resulting aqueous layer was twice extracted with CH2-
Cl2 (10 mL). The organic extracts were pooled, washed with brine (10
mL), dried (MgSO4), concentrated, and fractionated on a silica gel
column (eluent: CHCl3/EtOAc/hexanes, 3/1/1) to give the (S)S-isomer
31 (7.7 mg, 54%) and the (R)S-isomer 32 (1.2 mg, 8%). 31: [R] )
1H), 3.75 (dd, J ) 10.2 and 3.3 Hz, 1H), 3.47-3.56 (m, 1H), 3.31
(dd, J ) 13.5 and 6.9 Hz, 1H), 3.22 (dd, J ) 13.5 and 8.1 Hz, 1H);
13C NMR δ 128.7, 128.6, 128.4, 128.3, 128.0, 127.8, 126.5, 126.2,
123.4, 101.8, 91.3, 80.0, 78.9, 74.7, 73.6, 73.5, 73.3, 68.3; IR υ 1095,
1056, 1027; HRMS Calcd for C30H32NaO8S (M + Na)+: 543.1817,
found: 543.1847.
1
-50 (c ) 0.5); H NMR δ 7.30-7.52 (m, 15H), 5.90-6.04 (m, 1H),
General Protocol for Equilbration Experiments. The sulfoxides
(2-5 mg) were dissolved in either C6D6 or CD3OD (0.5 mL) in an
NMR tube and heated at 60 °C in an oil bath with periodic monitoring
5.63 (s, 1H), 5.49 (d, J ) 9.9 Hz, 1H), 5.38 (dd, J ) 17.7 and 0.9 Hz,
1H), 5.11 (d, J ) 10.5 Hz, 1H), 4.83 (d, J ) 10.5 Hz, 1H), 4.82 (d, J
) 12.3 Hz, 1H), 4.78 (d, J ) 12.3 Hz, 1H), 4.47 (dd, J ) 1.2 and 3.0
Hz, 1H), 4.22-4.33 (m, 3H), 3.86 (t, J ) 11.1 Hz, 1H), 3.77 (dd, J )
9.3 and 3.0 Hz, 1H), 3.71 (dd, J ) 13.2 and 6.3 Hz, 1H), 3.41-3.50
(m, 1H), 3.35 (dd, J ) 13.5 and 8.4 Hz, 1H); 13C NMR δ 138.1, 138.0,
137.4, 129.2, 128.8, 124.0, 101.8, 91.7, 78.9, 78.6, 76.3, 73.4, 72.9,
68.2, 52.3; IR υ 1095, 1043 cm-1; FABHRMS Calcd for C30H33O6S
(M + H)+: 521.1998, found: 521.1954. 32: 1H NMR δ 7.29-7.51
(m, 15H), 5.74-5.88 (m, 1H), 5.66 (s, 1H), 5.33 (d, J ) 10.2 Hz, 1H),
5.16 (d, J ) 16.5 Hz, 1H), 5.07 (d, J ) 11.4 Hz, 1H), 4.93 (d, J )
12.6 Hz, 1H), 4.84 (d, J ) 11.7 Hz, 1H), 4.76 (d, J ) 11.7 Hz, 1H),
4.34-4.41 (m, 3H), 4.27 (d, J ) 1.8 Hz, 1H), 3.93 (t, J ) 10.5 Hz,
1
by H- or 13C NMR analysis until equilibrium was attained.
Acknowledgment. We thank the NIH (GM 57335) for
support and Professors C. R. Johnson (Wayne State) and P.
Rollin (Orle´ans) for helpful discussions.
Supporting Information Available: Listings of the positional
and thermal parameters for 14 and 20 with bond distances and
angles for the non-hydrogen atoms (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0122694
9
6036 J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002