Solvent-dependent, kinetically controlled stereoselective synthesis of 3- and 4-thioglycosides

Article abstract of DOI:10.1021/jo050650r

Facile approaches to prepare 3- and 4-thioglycosides of the galacto, gulo, and gluco type from the parent triflates are presented. The dependencies of the solvent and the protecting group pattern, as well as the configuration of the neighboring and leavin

Full text of DOI:10.1021/jo050650r

Solvent-Dependent, Kinetically Controlled
Stereoselective Synthesis of 3- and
4-Thioglycosides
Zhichao Pei, Hai Dong, and Olof Ramstro¨m*
Department of Chemistry, Royal Institute of Technology,
Teknikringen 30, S-10044 Stockholm, Sweden
ramstrom@kth.se
Received April 3, 2005
FIGURE 1. Structures of glycoside triflates studied.
cosidases potentiating their use as efficient building
blocks in drug design and therapeutics.1 Special attention
has been put on the synthesis of 1-thiosaccharides and
their use in the synthesis of 1-thioglycosides, and to
broaden the scope for thiosaccharides in organic synthe-
sis, further studies involving nonanomeric analogues
need to be pursued.2,5,11,12
The present study describes convenient routes to 3- and
4-thioglycosides of the galacto, gulo, and gluco type, using
mainly ester protecting groups, from the reactions be-
tween the corresponding triflates and thioacetate. To
distinguish the neighboring group participation from the
ester moieties adjacent to the target position, four dif-
ferent carbohydrate reactants were chosen (Figure 1).
These exert representative combinations of axial-
equatorial relations between the participating ester and
triflate groups. Thus, methyl â-D-guloside- (1), methyl
â-D-galactoside- (2, 3), and methyl â-D-glucoside- (4)
derivatives were employed as reactants.13
Facile approaches to prepare 3- and 4-thioglycosides of the
galacto, gulo, and gluco type from the parent triflates are
presented. The dependencies of the solvent and the protect-
ing group pattern, as well as the configuration of the
neighboring and leaving groups, have been studied for these
reactions. The results clearly show that the efficient stereo-
selective synthesis of methyl 3-thio-galactoside depends
highly on the solvent and the nucleophile concentration.
Furthermore, the solvent dependence was studied
where either tetrabutylammonium thioacetate (TBASAc)
in toluene or CH2Cl2 or potassium thioacetate (KSAc) in
DMF was used.
Scheme 1 represents the synthetic route from starting
triflate 1 to generate 3-SAc-glycosides 52 and 7. The
reaction was found to be highly dependent on both the
solvent and the concentration of the thioacetate reagent.
When TBASAc in toluene was employed to displace the
OTf group, a straightforward SN2 reaction was antici-
pated in yielding the 3-SAc-glycoside 5 of the galactose
type. However, it was found that the corresponding
thioacetate of the gulose type (7) was formed in strong
competition with 5. Up to 40% 7 could be afforded in the
5/7 mixture, strongly dependent on the nucleophile
concentration. Table 1 summarizes this concentration
dependence. The yield of 5 could be dramatically in-
creased when the concentration of TBASAc was increased
to close to the saturation limit (40 equiv), resulting in
almost quantitative formation of 5.
Thiosaccharides, where an exocyclic oxygen is replaced
by a sulfur functionality, constitute an increasingly im-
portant group of compounds in glycochemistry, possess-
ing unique characteristics compared to their oxygen-con-
taining counterparts.1 These compounds are often used
as efficient glycoside donors and acceptors in oligosacchar-
ide and neoglycoconjugate synthesis,2-9 because the thio-
late is a potent nucleophile and a weak base that reacts
easily and selectively with soft electrophiles.10 Further-
more, the resulting thioglycosides and S-linked conju-
gates possess increased resistance to degradation by gly-
* To whom correspondence should be addressed. Phone: +46 8
7906915, Fax: +46 8 7912333.
(1) Driguez, H. ChemBioChem 2001, 2, 311-318.
(2) Rich, J. R.; Bundle, D. R. Org. Lett. 2004, 6, 897-900.
(3) Rye, C. S.; Withers, S. G. Carbohydr. Res. 2004, 339, 699-703.
(4) Zhu, X.; Stolz, F.; Schmidt, R. R. J. Org. Chem. 2004, 69, 7367-
7370.
(5) Liakatos, A.; Kiefel, M. J.; von Itzstein, M. Org. Lett. 2003, 5,
4365-4368.
(10) Norberg, T. In Modern Methods in Carbohydrate Synthesis;
Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic Publishers:
Amsterdam, 1996; pp 82-106.
(6) Greffe, L.; Jensen, M. T.; Chang-Pi-Hin, F.; Fruchard, S.;
O’Donohue, M. J.; Svensson, B.; Driguez, H. Chem. Eur. J. 2002, 8,
5447-5455.
(11) Rich, J. R.; Szpacenko, A.; Palcic, M. M.; Bundle, D. R. Angew.
Chem., Int. Ed. 2004, 43, 613-615.
(7) Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995-2999.
(8) Marcaurelle, L. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123,
1587-1595.
(12) Eisele, T.; Toepfer, A.; Kretzschmar, G.; Schmidt, R. R. Tetra-
hedron Lett. 1996, 37, 1389-1392.
(13) Pei, Z.; Dong, H.; Andre´, S.; Gabius, H. J.; Ramstro¨m, O.
Unpublished work.
(9) Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801-805.
10.1021/jo050650r CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/28/2005
6952
J. Org. Chem. 2005, 70, 6952-6955

SCHEME 1a
SCHEME 2a
a Reagents and conditions: (a) TBASAc, toluene, N2, rt, 4 h;
(b) DMF/KSAc or CH2Cl2/TBASAc, rt.
a Reagents and conditions: (a) KSAc, DMF, N2, rt, 8 h; (b)
TBASAc (<20 equiv), toluene, N2, rt, 4 h.
TABLE 1. Stereoselectivity in the Reaction of 1 and
Different TBASAc Concentrations
relative yield (%)
This phenomenon of solvent-dependent kinetic control
prompted the study of other possible configurational
isomers, and compounds 2-4 were subjected to the same
reactions as compound 1 (Scheme 2). When the 3-OTf-
galactose derivative 2 was employed, no competing
reactions and no concentration dependence were found
and all reactions with SAc nucleophiles proceeded
smoothly in DMF and toluene. Gulo-derivative 7 was
thus formed in good yield without any complications.
Likewise, reactions with 4-OTf-galactose derivative 3 in
either solvent resulted in the glucose derivative 9 without
any complicating side reactions. Both of these compounds
present a 3,4-cis configuration, for which the acetoxonium
intermediate is unlikely to form. Since no other species
were identified in the products, formation of the 2,3-
acetoxonium from 2 or the potential 4,6-acetoxonium ion
from 3 can be largely ruled out.
On the other hand, compound 4 displayed behavior
similar to that of 1. In DMF the reaction led to a reaction
mixture, whereas in toluene compound 10 was formed
in good yield. In this case, however, no apparent concen-
tration dependence was seen. Since the anti-diequatorial
configurational relation between the triflate and the ester
functionalities is less likely to produce an intermediate
acetoxonium ring (cf. 2), the main reason for this solvent
dependence is likely the six-membered acetoxonium ring
arising from 6-OBz group. The formation of this species
is, however, kinetically less favored than the correspond-
ing five-membered ring, and hence no concentration
dependence could be seen.
entry
TBASAc (equiv)
5
7
1
2
3
4
5
10
20
40
60
75
88
96
40
25
12
4
The main reason for this behavior is most likely
ascribed to the competing formation of an acetoxonium
intermediate (6) in the reaction pathway. When an ester
functionality in the axial 4-position is present, establish-
ing an anti-diaxial relationship between the ester and
the triflate, 6 may form slowly with time to compete with
the attacking thioacetate in nonpolar solvent. Preferred
nucleophilic attack on the acetoxonium ion from the axial
3-position will then open the 5-ring and produce the
gulose derivative. Attack at the equatorial 4-position
proved less favored, and no 4-SAc-glucose analogues were
identified in the reaction.
The increasing yield of galactose-derivative 5 with
increasing nucleophile concentration supports the notion
of competing inter- and intramolecular reaction path-
ways. In a nonpolar solvent (toluene), the formation of 6
is very slow, therefore favoring an intermolecular SN2
reaction that is dependent on the nucleophile concentra-
tion. Therefore, the formation of 5 is under kinetic control
in toluene. When the reaction was carried out at 50 °C
with 40 equiv of TBASAc, a 66:34 ratio of 5 and 7 was
obtained after workup, suggesting a thermodynamically
controlled formation of 7 at these conditions.
For comparison, a polar solvent was also tested and 1
was reacted with KSAc (5 equiv) in DMF. In this case,
mainly the hydrolysis product 8 was produced after
workup and neither product 5 nor 7 was formed. The
same behavior was found when TBASAc (40 equiv) was
used in CH2Cl2. However, compound 8 was also quickly
formed from 1 in the absence of thioacetate in CH2Cl2 or
DMF at room temperature.
This set of configurational isomers leads to the follow-
ing conclusions concerning neighboring group participa-
tion in these reactions: (i) an anti-diaxial relationship
between the ester and the triflate (1) likely leads to the
formation of a reasonably stabilized acetoxonium inter-
mediate in nonpolar solvent, (ii) axial-equatorial (2) or
equatorial-axial (3) relationships are unlikely to generate
J. Org. Chem, Vol. 70, No. 17, 2005 6953

Methyl 3-Thio-tetra-O-acetate-â-D-galactopyranoside (5).14
Yield 81%; 1H NMR (CDCl3, 400 MHz) δ 5.28 (d, 1 H, J4,5 ) 2.8
Hz, H-4), 5.03 (dd, 1 H, J1,2 ) 7.8 Hz, J2,3 ) 11.8 Hz, H-2), 4.44
(d, 1 H, J1,2 ) 7.8 Hz, H-1), 4.01-4.08 (m, 2 H, H-6), 3.99 (td, 1
H, J5,6 ) 6.7 Hz, H-5), 3.91 (dd, 1 H, J2,3 ) 11.8 Hz, J3,4 ) 3.0
Hz, H-3), 3.50 (s, 3 H, OMe), 2.30 (s, 1 H, SAc), 2.13 (s, 3 H,
SCHEME 3a
OAc), 2.05 (s, 3 H × 2, 2 × OAc); [R]22 +1.6 (c 0.1, CHCl3).
D
Methyl 3-Thio-tetra-O-acetate-â-D-gulopyranoside (7).
Yield 85%; 1H NMR (CDCl3, 400 MHz) δ 5.13 (dd, 1 H, J1,2
7.3 Hz, J2,3 ) 4.5 Hz, H-2), 5.01 (dd, 1 H, J4,3 ) 4.5 Hz, J4,5
2.0 Hz, H-4), 4.45 (d, 1 H, J1,2 ) 7.3 Hz, H-1), 4.27 (dd, J2,3
)
)
)
4.5 Hz, J3,4 ) 4.5 Hz, H-3), 4.12-4.18 (m, 2 H, H-6), 4.01 (td, 1
H, J5,4 ) 2.0 Hz, J5,6 ) 6.3 Hz, H-5), 3.46 (s, 3 H, OMe), 2.35 (s,
3 H, SAc), 2.10 (s, 3 H, OAc), 2.01 (s, 3, OAc), 1.98 (s, 3 H, OAc);
13C NMR (CDCl3, 125 MHz) δ 192 (SAc) 170.8, 170.0, 169.8
(3 × OAc), 100.6 (C-1), 72.0 (C-5), 70.0 (C-4), 68.6 (C-2), 62.7
a Reagents and conditions: (a) KSAc, DMF, N2, rt.
(C-6), 57.0 (OMe), 44.1 (C-3), 31.0 (SAc), 21.2 (3 × OAc); [R]22
any acetoxonium intermediates, (iii) an anti-diequatorial
relationship (2, 4) is likely inefficient in forming this
intermediate, (iv) the 4,6-anti-diequatorial relationship
in compound 4 may potentially form a moderately stable
intermediate in DMF, whereas (v) a 4,6-axial-equatorial
relation (3) is largely inefficient. As a comparison, an
alternative route to 3-SAc-galactosides, using the 4,6-O-
benzylidene 11 instead of ester protecting groups,5,12 was
followed (Scheme 3). In this case, compound 12 was
formed devoid of any complications in good yield in DMF
using KSAc as nucleophile. This supports the finding that
an axial ester functionality in the 4-position is the major
reason for competing reaction to occur and also supports
the lack of participation from the ester in the equatorial
2-position. In addition, compound 14 could be efficiently
obtained from compound 13 in DMF, supporting the
participation from the 6-OBz ester functionality in com-
pound 4. In the latter case, however, benzyl protecting
groups are less favorable in these syntheses, owing to
complications in deprotection by hydrogenation.
In conclusion, 3- and 4-SAc glycosides of the galacto,
gluco, and gulo series have been efficiently prepared
using simple nucleophilic substitution of the parent
triflates with thioacetate. The potential influence from
adjacent ester protecting groups has been mapped, and
the desired products could be formed in good yields in
all cases. Strong solvent dependence was especially found
for 3,4-anti-diaxial relationship between the ester and
the leaving group, but the galacto species could neverthe-
less be formed under kinetic control.
D
-11.8 (c 0.45, CHCl3). Anal. Calcd for C15H22O9S: C, 47.61; H,
5.86; S, 8.47. Found: C, 47.38; H, 5.77; S, 8.48.
Methyl 2,4,6-Tri-O-acetyl-â-D-galactopyranoside (8).15 1H
NMR (CDCl3, 400 MHz) δ 5.32 (d, 1 H, J3,4 ) 3.5 Hz, H-4), 4.95
(dd, 1 H, J1,2 ) 8.0 Hz, J2,3 ) 10.1 Hz, H-2), 4.35 (d, 1 H, J1,2
)
8.0 Hz, H-1), 4.15 (d, 2 H, J5,6 ) 6.7 Hz, H-6), 3.78-3.88 (m, 2
H, H-3, H-5), 3.51 (s, 3 H, OMe), 2.47 (d, 1 H, OH), 2.16 (s, 3 H,
OAc), 2.12 (s, 3 H, OAc), 2.05 (s, 3 H, OAc); 13C NMR (CDCl3,
125 MHz) δ 171.4, 171.0 (3 × OAc), 102.2 (C-1), 72.7 (C-2), 71.3
(2 × C, C-3, C-5), 70.2 (C-4), 62.4 (C-6), 57.2 (OMe), 21.3, 21.1
21.0 (3 × OAc); [R]22 -20 (c 0.2, CHCl3).
D
Methyl 2,3,6-Tri-O-benzoyl-4-S-acetyl-â-D-glucopyrano-
side (9). Yield 82%; 1H NMR (CDCl3, 400 MHz) δ 8.08-8.13
(m, 2 H, Ph), 7.86-7.96 (m, 4 H, Ph), 7.30-7.61 (m, 9 H, Ph),
5.72 (dd, 1 H, J2,3 ) 9.5 Hz, J3,4 10.8 Hz, H-3), 5.42 (dd, 1 H, J2,3
) 9.5 Hz, J1,2 ) 8.0 Hz, H-2), 4.70 (dd, 1 H, J5,6a ) 2.2 Hz, J6a,6b
) 12.1 Hz, H-6a,), 4.66 (d, 1 H, J1,2 ) 8.0 Hz, H-1), 4.56 (dd, 1
H, J5,6b ) 5.0 Hz, J6a,6b ) 12.1 Hz, H-6b), 4.12 (ddd, 1 H, J4,5
)
11.0 Hz, J5,6a ) 2.1 Hz, J5,6b ) 5.1 Hz, H-5), 4.04 (m, H-4), 3.50
(s, 3 H, OMe), 2.20 (s, 3 H, SAc); 13C NMR (CDCl3, 125 MHz) δ
192.5 (SAc) 166.1, 165.6, 165.1 (3 C, Ph-CdO), 134.1, 133.0,
132.9, 129.7, 129.6, 129.2, 128.7, 128.3, 128.2, 128.5, 128.1 (18
C, Ph), 101.7 (C-1), 72.8 (C-5), 72.7 (C-2), 71.6 (C-3), 63.7 (C-6),
56.8 (OMe), 44.4 (C-4), 30.5 (SAc); [R]22D +45 (c 0.4, CHCl3). Anal.
Calcd for C30H28O9S: C, 63.82; H, 5.00; S, 5.68. Found: C, 63.59;
H, 5.01; S, 5.57.
Methyl 2,3,6-Tri-O-benzoyl-4-S-acetyl-â-D-galactopyra-
noside (10). Yield 81%; 1H NMR (CDCl3, 400 MHz) δ 7.85-
8.15 (m, 6H, Ph), 7.28-7.62 (m, 9 H, Ph), 5.64 (dd, 1 H, J2,3
10.1 Hz, J3,4 ) 4.5 Hz, H-3), 5.46 (dd, 1 H, J2,3 ) 10.1 Hz, J1,2
)
)
7.68 Hz, H-2), 4.61-4.72 (m, 3 H, H-6a, H-4, H-1), 4.43 (dd, 1
H, J5,6b ) 6.0 Hz, J6a,6b ) 11.2 Hz, H-6b), 4.37 (td, 1 H, J5,6
)
6.3 Hz, J4,5 ) 1.4 Hz, H-5), 3.51 (s, 3 H, OMe), 2.27 (s, 3 H, SAc);
13C NMR (CDCl3, 125 MHz) δ 192.9 (SAc) 166.1, 165.5, 165.2 (3
C, Ph-CdO), 133.4, 133.3, 133.2, 129.8, 129.7, 129.6, 129.5, 129.4,
129.1, 128.5, 128.4 (18 C, Ph), 102.7 (C-1), 71.8 (C-3), 71.5
(C-5), 70.7 (C-2), 63.6 (C-6), 57.0 (OMe), 46.5 (C-4), 30.6 (SAc);
[R]22D -4.5 (c 0.8, CHCl3). Anal. Calcd for C30H28O9S: C, 63.82;
H, 5.00; S, 5.68. Found: C, 63.63; H, 4.92; S, 5.56.
Experimental Section
General Synthesis of Triflate Derivatives. To a solution
of the suitably O-protected methyl â-D-glycoside,13 carrying an
unprotected OH at C-3 or C-4 (0.3 g, 0.94 mmol), in CH2Cl2 (5
mL) was added pyridine (0.65 mL) at -20 °C. Trifluoromethane-
sulfonic anhydride (0.53 g, 1.88 mol) in CH2Cl2 (2 mL) was added
dropwise, and the mixture was stirred and allowed to warm from
-20 to 10 °C over 2 h. The resulting mixture was subsequently
diluted with CH2Cl2 and washed with 1 M HCl, aqueous
NaHCO3, water, and brine. The organic phase was dried over
Na2SO4 and concentrated in vacuo at low temperature. The
residue was used directly in the next step without further
purification.
General Synthesis of Thiolacetate Derivatives. TBASAc
or KSAc (1-40 equiv) was added to a solution of the protected
triflate residue (10 mg) in dry toluene, CH2Cl2, or DMF (1.0 mL),
respectively. After stirring at room temperature for 4 h, the
mixture was diluted with ethyl acetate and washed with brine.
The organic phase was dried with MgSO4 and concentrated in
vacuo. Purification of the residue by flash column chromato-
graphy (3:2 hexanes-ethyl acetate) afforded the thiolacetate
derivative.
Methyl 2,3,6-Tri-O-benzyl-4-S-acetyl-â-D-galactopyrano-
1
side (14). Yield 83%; H NMR (CDCl3, 400 MHz) δ 7.16-7.35
(m, 15 H, Ph), 4.83 (d, 1 H, J 11.0 Hz, Ph-CH2), 4.76 (d, 1 H, J
11.0 Hz, Ph-CH2), 4.57 (d, 1 H, J 11.0 Hz, Ph-CH2), 4.36-4.53
(m, 4 H, 3 × PhCH2, H-4), 4.31 (d, 1 H, J1,2 7.7 Hz, H-1), 3.88
(dt, 1 H, J5,6 5.7 Hz, H-5), 3.82 (dd, 1 H, J2,3 9.5 Hz, J3,4 4.4 Hz,
H-3), 3.52-3.66 (m, 2 H, H-6) 3.49 (s, 3 H, OMe), 3.16-3.25 (m,
1H, H-2), 2.32 (s, 3 H, SAc); 13C NMR (CDCl3, 125 MHz) δ 195.0
(SAc) 139.0, 138.3, 138.3 (3 C, Ph), 128.0-129.0 (15 C, Ph) 105.5
(C-1), 81.0 (C-2), 79.8 (C-3), 75.8, 74.1 (2 × Ph-CH2), 73.2 (C-5),
72.4 (Ph-CH2), 70.5 (C-6), 57.7 (OMe), 46.8 (C-4), 31.3 (SAc);
[R]22D -1.6 (c 0.1, CHCl3). Anal. Calcd for C30H34O6S: C, 68.94;
(14) Tsuda, Y.; Noguchi, S.; Kanemitsu, K.; Sato, Y.; Kakimoto, K.;
Iwakura, Y.; Hosoi, S. Chem. Pharm. Bull. 1997, 45, 971-980.
(15) Kajihara, Y.; Kodama, H.; Endo, T.; Hashimoto, H. Carbohydr.
Res. 1998, 306, 361-378.
6954 J. Org. Chem., Vol. 70, No. 17, 2005

H, 6.56; S, 6.14. Found: C, 68.94; H, 6.63; S, 6.25. HRMS for
Supporting Information Available: General methods;
NMR spectra of stereoselective reactions of 1 with TBASAc;
and 1H, 13C, 1H-1H (COSY), and 1H-13C (HMQC) NMR
spectra of compound 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
C
30H34O6S 545.19738 (M + Na), found 545.19807.
Acknowledgment. This study was supported by the
Swedish Research Council, the Swedish Foundation for
International Cooperation in Research and Higher
Education, and the Carl Trygger Foundation.
JO050650R
J. Org. Chem, Vol. 70, No. 17, 2005 6955