Studies on the latter process revealed the occurrence of a
lactol intermediate formed by selective oxidation of the
primary hydroxyl function and ensuing nucleophilic attack
of the secondary alcohol on the resulting aldehyde. In the
next oxidation cycle, the lactol is oxidized to the lactone.7
We recently demonstrated the efficacy of the TEMPO/
BAIB reagent system in the chemo- and regioselective
oxidation of a variety of 4,6-dihydroxy 1-thioglycosides (3,
Figure 1B).8 The 1-thio uronic esters (5), obtained by
treatment of 4 with diazomethane, proved to be valuable
building blocks in oligosaccharide synthesis.9
In an extension of the above-described method for the
selective oxidation of 4,6-dihydroxy 1-thioglycosides, we
here report on a tandem oxidation-lactonization process of
a variety of 2,6- and 3,6-dihydroxy 1-thioglycosides and
application of the resulting 6,2- and 6,3-lactones in oligosac-
charide synthesis.
Changing the reaction medium to the biphasic dichlo-
romethane/water system led to the rapid and efficient
transformation of diol 6 to lactone 7 (75% yield) with only
trace amounts of side-products formed. Subjection of ethyl
3,4-di-O-benzyl-1-thio-R-D-mannopyranoside 9, having a
2,6-cis-diol configuration, to the latter oxidation conditions
afforded lactone product 10 in 77% yield. Similarly, glyco-
pyranosides 12 and 15 were converted into lactones 13 and
16 (entries 3 and 4). The relatively poor yield in transforming
glucopyranoside 15 into lactone 16 is likely due to the change
from the “all-equatorial” C1 conformation into the C4
conformation having all substituents in an axial orientation.
As a final example, compound 18 containing an anomeric
hydroxyl group was converted into the corresponding 6,1-
lactone 19, albeit in moderate yield (27%).
Our next objective was to identify suitable conditions for
selective opening of the lactone bridge, liberating a hydroxyl
function for potential functionalization in ensuing glycosy-
lation events. Stirring compounds 10 and 13 in anhydrous
methanol under a gentle reflux furnished the corresponding
transesterified products 11 and 14 (entries 2 and 3) in a
quantitative yield. As exemplified in entry 3, the relatively
labile acetyl group is stable with respect to the cleavage
conditions of the lactone bridge.11 The lactone function in
compounds 7 and 16 (entries 1 and 4) could not be opened
under these conditions, most likely due to steric hindrance
of the bulky benzyl and thiophenyl groups. However, stirring
7 and 16 in methanol and a catalytic amount of p-
toluenesulfonic acid at ambient temperature delivered the
desired esters 8 and 17, respectively, in a quantitative
yield.
4
1
In a first attempt to induce lactone formation (Table 1,
entry 1), phenyl 2,3-di-O-benzyl-1-thio-â-D-galactopyrano-
Table 1.
The conformationally locked lactones (7, 10, 13, 16) bear
promising properties in stereoselective glycosylation.12 It is
now well established that the conformation of donor glyco-
sides can play a pivotal role in governing both reactivity
and anomeric selectivity in glycosidations. For example,
Fraser-Reid and co-workers reported that benzylidene-
protected glycosides are less reactive than their benzylated
counterparts.13 This difference in reactivity stems from
“torsional disarmament” and has been exploited to increase
anomeric selectivities.14 It has been stated that, in a glyco-
sylation event, torsional effects are, in general, overruled by
(7) For a comprehensive review on the mechanism of TEMPO oxidations,
see: De Nooy, A. E. J.; Besemer, A. C.; Van Bekkum, H. Synthesis 1996,
1153-1174.
(8) Van den Bos, L. J.; Code´e, J. D. C.; Van der Toorn, J. C.; Boltje, T.
J.; Van Boom, J. H.; Overkleeft, H. S.; Van der Marel, G. A. Org. Lett.
2004, 6, 2165-2168.
a Conditions: 0.2 equiv of TEMPO, 2.5 equiv of BAIB, DCM, rt.
b Conditions: 0.2 equiv of TEMPO, 2.5 equiv of BAIB, DCM/H2O (2:1),
rt. c Conditions: MeOH, reflux. d Conditions: catalytic H+, MeOH, rt.
e Isolated yields.
(9) For a review on the oxidation of carbohydrates using TEMPO, see:
Bragd, P. L.; Van Bekkum, H.; Besemer A. C. Top. Catal. 2004, 27, 49-
66.
(10) Formation of the lactone ring was confirmed by the change in
coupling constant between H-1 and H-2. The doublet in compound 6 (3J1,2
) 7.1 Hz) was transposed into a singlet after the oxidation-lactonization
process.
(11) (a) Chernyak, A. Y.; Kononov, L. O.; Kochetkov, N. K. Carbohydr.
Res. 1992, 216, 381-398. (b) Kornilov, A. V.; Sherman, A. A.; Kononov,
L. O.; Shashkov, A. S.; Nifant’ev, N. E. Carbohydr. Res. 2000, 329, 717-
730.
(12) For a related study on the use of 6,1-lactones, see: Pola´kova´, M.;
Pitt, N.; Tosin, M.; Murphy, P. V. Angew. Chem., Int. Ed. 2004, 116, 2572-
2575.
side 6 was treated with 0.2 equiv of TEMPO and 2.5 equiv
of BAIB in anhydrous dichloromethane. The expected 6,3-
lactone10 7 was obtained in 54% yield along with a
considerable amount of sulfoxide and sulfone byproducts.
(6) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J. H.; Abrams,
J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57-59.
(13) Fraser-Reid, B.; Wu, Z. F.; Andrews, C. W.; Skowronski, E.; Bowen,
J. P. J. Am. Chem. Soc. 1991, 113, 1434-1435.
2008
Org. Lett., Vol. 7, No. 10, 2005