Stereoselective sulfoxidation of α-mannopyranosyl thioglycosides: The exo-anomeric effect in action

Article abstract of DOI:10.1039/a804126a

As a consequence of the exo-anomeric effect, and in contrast to their β-anomers, α-thioglycosides undergo stereoselective oxidation to give very predominantly the R-sulfoxides, as revealed by X-ray crystallography.

Full text of DOI:10.1039/a804126a

Stereoselective sulfoxidation of a-mannopyranosyl thioglycosides: the
exo-anomeric effect in action
David Crich,*a Jan Mataka,a Sanxing Sun,a K.-C. Lam,b Arnold L. Rheingoldb and Donald J. Winka
a Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA.
E-mail: dcrich@uic.edu
b Department of Chemistry and Biochemistry, University of Delaware, Academy Street, Newark, DE 19716, USA
Received (in Corvallis, OR, USA) 29th May 1998, Accepted 10th November 1998
X
X
As a consequence of the exo-anomeric effect, and in contrast
to their b-anomers, a-thioglycosides undergo stereoselective
oxidation to give very predominantly the R-sulfoxides, as
revealed by X-ray crystallography.
O
O
Ph
O
O
Ph
O
O
O
O
O
O
Y
Y
R
R
S
S
O
The sulfoxide method is a very powerful tool for the formation
of glycosidic linkages to even very sterically hindered,
unreactive glycosyl acceptors.1–3 In most of the work described
in the literature b-thioglycosides are oxidized to mixtures of
sulfoxides,3–5 which are used as such in the coupling reaction.
In contrast, we have noted that a range of differentially
protected a-mannopyranosyl thioglycosides are oxidized with
excellent stereoselectivity to give essentially diastereomerically
pure sulfoxides. These may then be employed productively in
the efficient synthesis of b-mannopyranosides.6–9 We now
report the configuration of three a-mannopyranosyl sulfoxides,
as determined by X-ray crystallography and chemical correla-
tion, and discuss a possible reason for the stereoselectivity.
Initially, we noted that thioglycoside 1 was oxidized
stereoselectively by magnesium monoperoxyphthalate
(MMPP) in aqueous THF to give a single sulfoxide 8 in
excellent yield, but were unable to assign configuration.10
Similar results were obtained with MCPBA in CH2Cl2.
Subsequently, the same phenomenon was observed with
thioglycosides 2–7 and 15–17, giving the corresponding
sulfoxides 9–14 and 18–20.6–9,11,12 In view of the mechanism of
the stereoselective b-mannosylation process,9 in which the
sulfoxide simply serves as a convenient precursor to the actual
glycosylating species, the a-mannosyl triflate, the configuration
at sulfur is of no consequence. However, curiosity dictated that
we seek the origins of this unanticipated stereoselective
sulfoxidation. Eventually, we were rewarded by the growth of
single crystals of 20 (mp 109–111 °C) suitable for X-ray
crystallographic analysis from EtOH solution. In due course the
configuration at sulfur was revealed to be R (Fig. 1).
1 R = Et, X = TBDMS, Y = Bn
2 R = Et, X = TMS, Y = Bn
3 R = Et, X = Y = Bn
8
9
R = Et, X = TBDMS, Y = Bn
R = Et, X = TMS, Y = Bn
10 R = Et, X = Y = Bn
11 R = Ph, X = Y = Bn
12 R = Et, X = Y = allyl
13 R = Et, X = allyl, Y = Bn
14 R = Ph, X = Y = Me
4 R = Ph, X = Y = Bn
5 R = Et, X = Y = allyl
6 R = Et, X = allyl, Y = Bn
7 R = Ph, X = Y = Me
X
X
O
O
O
O
O
X
O
O
O
O
O
X
R
Et
S
S
17
15 R = Et, X = Bn
16 R = Ph, X = Me
X
X
O
O
O
X
O
O
O
O
X
O
R
O
S
O
O
Et
S
18 R = Et, X = Bn
19 R = Ph, X = Me
O
20
In an attempt to obtain an isomeric sulfoxide, 16 was
oxidized with NaIO4 and with Oxone, but in each case only 19
was obtained. It was therefore apparent that the stereoselectivity
was not a function of the reagent and, for example, hydrogen
bonding to the ring oxygen. We next submitted thioglycoside 21
to oxidation with MCPBA and again were rewarded by the
formation of one major sulfoxide ( > 10:1). Crystals suitable for
X-ray analysis were again obtained (mp 190 °C, EtOH) and the
structure consequently revealed to be 22 (Fig. 2), with the same
configuration at sulfur as 20. Again, a diverse range of oxidants
provided the same major sulfoxide. Treatment of 22 with NaH
and then BnBr in THF provided sulfoxide 10, albeit in only 35%
yield, so fixing its configuration at sulfur as R. Thus, we have
established that three of the eleven sulfoxides in question have
the same R-configuration and see no reason to doubt that the
remainder follow the pattern.
OH
O
OH
O
Ph
O
O
Ph
O
O
O
O
H
H
Et
Et
S
S
O
21
22
steric effects13 and the conformation imposed on the thioglyco-
sides by the exo-anomeric effect.14–16 Thus, as seen from the
Newman projection in Fig 3, in the conformation imposed by
the exo-anomeric effect the pro-R lone pair of the a-
thioglycosides is exposed to attack. On the other hand oxidation
of the pro-S lone pair would be substantially hindered by the
pyranose ring, and especially by the axial hydrogens, H-3 and
H-5. In the case of the b-thioglycosides, the two lone pairs are
less sterically differentiated and mixtures of sulfoxides result.
Finally, we note that the two crystalline sulfoxides both adopt
the same conformation (Fig. 1 and 2) about the C1–S bond,
which roughly mirrors that imposed on the original thioglyco-
In view of the range of different oxidants and solvents
employed, each giving the same result, we conclude that the
stereoselectivity of the oxidation is dictated predominantly by
Chem. Commun., 1998, 2763–2764
2763

Notes and references
1 R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N.
Horan, J. Gildersleeve, C. Thompson, A. Smith, K. Biswas, W. C. Still
and D. Kahne, Science, 1996, 274, 1520.
2 D. Kahne, S. Walker, Y. Cheng and D. V. Engen, J. Am. Chem. Soc.,
1989, 111, 6881.
3 L. Yan and D. Kahne, J. Am. Chem. Soc., 1996, 118, 9239.
4 R. Kakarla, R. G. Dulina, N. T. Hatzenbuhler, Y. W. Hui and M. J.
Sofia, J. Org. Chem., 1996, 61, 8347.
5 However, we note that the two unprotected b-galactosyl phenyl
sulfoxides are hydrolyzed at different rates by aqueous TfOH,
presumably due to differential intramolecular hydrogen bonding
interactions: N. Khiar, I. Alonso, N. Rodriguez, A. Fernandez-
Mayorales, J. Jimenez-Barbero, O. Nieto, F. Cano, C. Foces-Foces and
M. Martin-Lomas, Tetrahedron Lett., 1997, 38, 8267.
6 D. Crich and S. Sun, Tetrahedron, 1998, 54, 8321.
7 D. Crich and S. Sun, J. Org. Chem., 1996, 61, 4506.
8 D. Crich and S. Sun, J. Org. Chem., 1997, 62, 1198.
9 D. Crich and S. Sun, J. Am. Chem. Soc., 1997, 119, 11217.
10 D. Crich, S. Sun and J. Brunckova, J. Org. Chem., 1996, 61, 605.
11 D. Crich and Z. Dai, Tetrahedron Lett., 1998, 53, 1681.
12 A further, unassigned example of diastereoselective sulfoxidation of an
a-mannosyl thioglycoside: G. Stork and J. J. La Clair, J. Am. Chem.
Soc., 1996, 118, 247.
Fig. 1 Structure of 20 showing crystallographic numbering scheme
adopted.
13 C. R. Johnson and D. McCants, J. Am. Chem. Soc., 1965, 87, 1109.
14 E. Juaristi and G. Cuevas, The Anomeric Effect, CRC Press, Boca Raton,
1995.
15 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon, Oxford, 1983.
16 A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen, Springer-Verlag, Berlin, 1983.
Fig. 2 Structure of 22 showing crystallographic numbering scheme
adopted.
17 Crystal data for 20: C14H24O6S, M
= 320.39, monoclinic, a =
11.282(7), b = 9.766(10), c = 15.555(12) Å, b = 99.73(6)°, V =
1689(2) Å3; P21, Z = 4 (two independent molecules per asymmetric
unit), m
=
0.22 mm21. Of 3381 reflections measured at room
P
temperature, 3163 independent reflections were used in refinement on
F2. Final agreement factors for 390 least-squares parameters for 1887
data with I > 2 s(I) (with values for all independent reflections in
parentheses): R = 0.0412 (0.0830), Rw = 0.0984 (0.1217), GOF =
1.032 (1.131). For 22: C15H20O6S, M = 328.37, monoclinic, a =
5.1509(2), b = 12.9187(4), c = 11.4762(5), b = 95.554(2)°, V =
760.07(8) Å3, P21, Z = 2. m = 0.24 mm21. Of 2613 reflections
measured at T = 173 K, there were 1718 independent reflections used
in refinement against F2 with 1551 having I > 2s(I). Final agreement
factors for 199 least-squares parameters (with values for all independent
reflections in parentheses): R = 0.0864 (0.1039), wR2 = 0.2847
(0.2582), GOF = 2.415 (2.414). CCDC 182/1088. The crystallographic
data is available as a .cif file: see http://www.rsc.org/suppdata/cc/
1998/2763/
P
O
R
O
O
O
P
O
=
O
P
R
S
P = protecting group or H
Fig. 3
sides by the exo-anomeric effect. However, in this instance, it
seems likely that this is more a consequence of minimization of
repulsion between the C1–O5 and S–O dipoles.17
We thank the NSF (CHE 9625256 and NIH GM57335) for
partial support of this work.
Communication 8/04126A
2764
Chem. Commun., 1998, 2763–2764