Preparation of 1-thio uronic acid lactones and their use in oligosaccharide synthesis

Article abstract of DOI:10.1021/ol050491y

(Chemical Equation Presented) The chemo- and regioselective TEMPO/BAIB-mediated oxidation of 2,6- and 3,6-dihydroxy 1-thio glycopyranosides to the corresponding 1-thio uronic acid lactones is described. These locked 1-thio glycuronides can directly be use

Full text of DOI:10.1021/ol050491y

ORGANIC
LETTERS
2005
Vol. 7, No. 10
2007-2010
Preparation of 1-Thio Uronic Acid
Lactones and Their Use in
Oligosaccharide Synthesis
Leendert J. van den Bos, Remy E. J. N. Litjens,
Richard J. B. H. N. van den Berg, Herman S. Overkleeft, and
Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502,
2300 RA Leiden, The Netherlands
g.marel@chem.leidenuniV.nl
Received March 7, 2005
ABSTRACT
The chemo- and regioselective TEMPO/BAIB-mediated oxidation of 2,6- and 3,6-dihydroxy 1-thio glycopyranosides to the corresponding 1-thio
uronic acid lactones is described. These locked 1-thio glycuronides can directly be used as donors in glycosidation reactions using the
Ph2SO/Tf2O reagent system. Alternatively, selective opening of the lactone bridge liberates a hydroxyl function for ensuing glycosylations.
The 2,2,6,6-tetramethylpiperidinyloxy free radical 1 (TEMPO,
Figure 1A) is a versatile and often applied reagent for the
selective oxidation of primary hydroxyl functions. The active
species in this reaction is believed to be the N-oxoammonium
salt 2, generated in situ from reaction between TEMPO (1)
and any of a number of co-oxidants. Many co-oxidants have
been used, for instance, m-chloroperoxybenzoic acid,1 cal-
cium or sodium hypochlorite,2 and several hypervalent
iodine(III) species.3 Piancatelli and co-workers revealed that
(1) (a) Cella, J. A.; Kelley, J. A.; Kenhan, E. F. J. Org. Chem. 1975, 40,
1860-1862. (b) Ganem, B. J. Org. Chem. 1975, 40, 1998-2000. (c) Cella,
Figure 1. TEMPO/BAIB-mediated chemo- and regioselective
J. A.; McGrath, J. P.; Kelley, J. A.; El Soukkary, O.; Hilpert, L. J. Org.
oxidation.
Chem. 1977, 42, 2077-2080.
(2) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559-2562. (b) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S.
J. Org. Chem. 1989, 54, 2970-2972. (c) Siedlecka, R.; Skarzewski, J.;
the combination of TEMPO and [bis(acetoxy)iodo]benzene
Mlochowski, J. Tetrahedron Lett. 1990, 31, 2177-2180. (d) Davis, N. J.;
(BAIB) enabled the chemo- and regioselective oxidation of
primary alcohols into the corresponding aldehydes.4,5 The
Forsyth group used the same reagent combination for the
synthesis of δ-lactones from the corresponding 1,5-diol
systems having a primary and secondary hydroxyl function.6
Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181-1184. (e) De Nooy, A. E.
J.; Besemer, A. C.; Van Bekkum, H. Carbohydr. Res. 1995, 269, 89-98.
(f) Haller, M.; Boons, G.-J. J. Chem. Soc., Perkin Trans. 1 2001, 814-
822. (g) Litjens, R. E. J. N.; Den Heeten, R.; Timmer, M. S. M.; Overkleeft,
H. S.; Van der Marel, G. A. Chem. Eur. J. 2005, 11, 1010-1016.
(3) (a) Spyroudis, S.; Varvoglis, A. Synthesis 1975, 445-447. (b)
Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1977, 50, 2773-2776. (c) Muller, P.; Godoy, J. Tetrahedron Lett. 1981,
22, 2361-2364. (d) Muller, P.; Godoy, J. HelV. Chim. Acta 1983, 66, 1790-
1795. (e) Togo, H.; Aoki, M.; Kuramochi, T.; Yokoyama, M. J. Chem.
Soc., Perkin Trans. 1 1993, 2417-2427. (f) Magnus, P.; Lacour, J.; Evans,
P. A.; Roe, M. B.; Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406-3418.
(4) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G.
J. Org. Chem. 1997, 62, 6974-6977.
(5) Oxidation toward the carboxylic acid, see: Epp, J. B.; Widlanski, T.
S. J. Org. Chem. 1999, 64, 293-295.
10.1021/ol050491y CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/20/2005

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

Table 2.
a Isolated yields. b Performed with 2.5 equiv of TTBP. c Performed with 1 equiv of TTBP.
the electronic effects exerted by the ring substituents.15 At
the same time, Bols and co-workers demonstrated that, in
the case of C4-locked methyl 3,6-anhydro-â-D-glycosides,
°C gave full activation within 15 min. Addition of acceptor
20, bearing a primary hydroxyl group, afforded disaccharide
21 in a near quantitative yield. Spectroscopic analysis
revealed the presence of an R-interglycosidic linkage. This
anomeric outcome is in accord with earlier studies showing
that the coupling of “disarmed” gluco- and galactopyranosyl
donors with disarmed acceptors proceeds in an R-selective
fashion.8,18 Analogously, methyl uronate 22 was applied as
an acceptor species in the Ph2SO/Tf2O-mediated glycosida-
tion involving donor 7, resulting in R-selective formation of
disaccharide 23 in 91% yield (entry 2). Changing the acceptor
toward N-(benzyloxycarbonyl)-protected glucosamine 24 also
delivered, fully R-selectively, the corresponding disaccharide
25. This reaction proceeded slower compared to the other
glycosidations, probably due to reduced reactivity of the
acceptor alcohol via intramolecular H-bonding.19 The amount
of base (TTBP) used in this condensation was reduced to 1
equiv with respect to the amount of Tf2O to circumvent
possible side-reactions involving the nucleophilic N-atom.20
Performing the reaction in the absence of base gave no
significant rise in yield. Upon addition of galactopyranose
26 to the activated mixture of donor 7, Ph2SO, and Tf2O, a
4:1 mixture of R- and â-disaccharides 27 was formed (entry
4). The reduced stereoselectivity may be related to the axial
orientation of OH-4 in acceptor 26, hampering the formation
of the R-product.21
1
the reactivity of the anomeric function is influenced by
electronic effects originating from the orientation of the
remaining hydroxy substituents.16 In this respect, we previ-
ously found that the remotely attached carboxylic ester on
the 6-position decreases the nucleophilicity of the sulfur atom
at the anomeric center.8 The intrinsic low reactivity of these
1-thio methyl uronates could be overcome by activation with
the highly electrophilic Ph2SO/Tf2O reagent combination at
slightly elevated temperature (-40 °C) compared to the
standard activation temperature (-60 °C).17 Galactosyl donor
7 was chosen as a model compound to determine the
influence of the bridged lactone function in glycosidation
reactions (Table 2). Treatment of lactone 7 with 1.3 equiv
of Ph2SO, 1.3 equiv of Tf2O, and 2.5 equiv of TTBP at -50
(14) (a) Grice, P.; Ley, S. V.; Pietruszka, J.; Osborn, H. M. I.; Priepke,
H. W. M.; Warriner, S. L. Chem. Eur. J. 1997, 3, 431-440. (b) Douglas,
N. L.; Ley, S. V.; Lu¨cking, U.; Warriner, S. L. J. Chem. Soc., Perkin Trans.
1 1998, 51-66. (c) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A.
C.; Ince, S. J.; Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101,
53-80. (d) Litjens, R. E. J. N.; Leeuwenburgh, M. A.; Van der Marel, G.
A.; Van Boom, J. H. Tetrahedron Lett. 2001, 42, 8693-8696. (e) Crich,
D.; De la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68, 8142-8148. (f)
Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004, 126,
9205-9213.
(15) Dean, K. E. S.; Kirby, A. J.; Komarov, I. V. J. Chem. Soc., Perkin
Trans. 2 2002, 337-341.
(16) Bols and co-workers found that 1C4-locked methyl 3,6-anhydro-â-
D-glucoside hydrolyzes much faster than the corresponding nonlocked 4C1
methyl â-D-glucoside: McDonnell, C.; Lo´pez, O.; Murphy, P.; Ferna´ndez
Bolan˜os, J. G.; Hazell, R.; Bols, M. J. Am. Chem. Soc. 2004, 126, 12374-
12385.
(18) (a) Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297-1300 and
references therein. (b) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E.
J. N.; Overkleeft, H. S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett.
2003, 5, 1947-1950. (c) Code´e, J. D. C.; Stubba, B.; Schiattarella, M.;
Overkleeft, H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der Marel,
G. A. J. Am. Chem. Soc. 2005, 127, 3767-3773.
(19) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819-6825.
(20) Van den Bos, L. J.; Code´e, J. D. C.; Van Boom, J. H.; Overkleeft,
H. S.; Van der Marel, G. A. Org. Biomol. Chem. 2003, 4160-4165.
(17) (a) Code´e, J. D. C.; Litjens, R. E. J. N.; Den Heeten, R.; Overkleeft,
H. S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1519-
1522. (b) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der Marel, G. A.
Tetrahedron 2003, 60, 1057-1064.
Org. Lett., Vol. 7, No. 10, 2005
2009

Having established that locked 1-thio uronic acid lactones
can be used as donors in glycosylation reactions, we set out
to explore their acceptor properties after opening of the
lactone bridge. Disaccharide 25 was taken as a model
compound toward the synthesis of nonnatural trisaccharide
30 (Scheme 1). Treatment of benzylated lactone 25 with
tivation of 2-O-acylated donor 29 using diphenylsulfonium
bistrifluoromethanesulfonate at -60 °C in dichloromethane
followed by addition of acceptor 28 afforded trisaccharide
30 in 63% yield. The regular acid scavenger TTBP was
excluded from the reaction mixture to prevent putative ortho
ester formation.
In summary, we have developed an efficient route for the
synthesis of locked 1-thio 6,2- and 6,3-lactones and their
implementation as both donor and acceptor in Ph2SO/Tf2O-
mediated coupling reactions. Further research is being
devoted to comparing the open 1-thio uronic acids with their
corresponding locked forms and the implementation of these
1-thio uronates in the synthesis of complex oligosaccharides.
Scheme 1
Acknowledgment. The authors thank Kees Erkelens and
Fons Lefeber for recording NMR spectra and Bertil Hofte
for measuring accurate mass spectra. This work was sup-
ported by the Council for Chemical Sciences of The
Netherlands Organization for Scientific Research (CW-
NWO).
Supporting Information Available: General procedures
and characterizations of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
potassium tert-butoxide in MeOH, under strictly anhydrous
conditions, afforded in 82% the desired acceptor 28. Preac-
(21) Spijker, N. M.; Van Boeckel, C. A. A. Angew. Chem., Int. Ed. Engl.
1991, 30, 180-183.
OL050491Y
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Org. Lett., Vol. 7, No. 10, 2005