Iodine monochloride/silver trifluoromethanesulfonate (ICI/AgOTf) as a convenient promoter system for O-glycoside synthesis

Article abstract of DOI:10.1021/ol015547c

matrix presented The novel promoter system iodine monochloride/silver trifluoromethanesulfonate (ICI/AgOTf) was evaluated with various thioglycoside donors and saccharide acceptors, and O-glycosides were obtained in 46-82% yield. Several practical advanta

Full text of DOI:10.1021/ol015547c

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1519-1522
Ph2SO/Tf2O: a Powerful Promotor
System in Chemoselective
Glycosylations Using Thioglycosides
Jeroen D. C. Code´e,† Remy E. J. N. Litjens,† Rene´ den Heeten,
Herman S. Overkleeft, Jacques H. van Boom, and Gijs 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 February 21, 2003
ABSTRACT
Diphenylsulfoxide in combination with triflic anhydride provides a very potent thiophilic glycosylation promotor system, capable of activating
disarmed thioglycosides. The usefulness of this novel thiophilic activator is illustrated in a successful chemoselective glycosylation sequence
in which the donor thioglycoside in the first condensation step may be either armed or disarmed.
Oligosaccharides and glycoconjugates, carbohydrate-based
biomolecules with broad structural diversity, play a crucial
role in a multitude of important biological processes.1 Despite
the recent advances in oligosaccharide synthesis,2 there still
is a demand for efficient and stereoselective glycosylation
procedures. Thioglycosides have been shown to be attractive
building blocks for the construction of oligosaccharides.2d,e
Thus, the anomeric thiogroup may not only function as a
protecting group but also as a leaving group in the formation
of interglycosidic linkages. In addition, the glycosylating
properties of thioglycosides can be tuned by varying the
nucleophilicity of the anomeric sulfur atom3 as well as the
electron-withdrawing and -donating effects inherent to the
protecting groups in the donor glycoside.4 The difference in
reactivity of thioglycosides can be exploited elegantly in a
chemoselective glycosylation, in which a reactive (“armed”)
(3) (a) Sliedregt, L. A. J. M.; Zegelaar-Jaarsveld, K.; Van der Marel, G.
A.; Van Boom, J. H. Synlett 1993, 335-337. (b) Boons, G. J.; Geurtsen,
R.; Holmes, D. Tetrahedron Lett. 1995, 6325-6328.
(4) Reactivities of glycosyl donors can be tuned. For thioglycosides,
see: (a) Douglas, N. L.; Ley, S. V.; Lu¨cking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51-65. (b) Zhang, Z.; Ollmann, I. R.; Ye,
X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999,
121, 734-753. (c) Burkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong,
C.-H. Angew. Chem., Int. Ed. 2001, 40, 1274-1277. (d) Mong, K.-K. T.;
Wong, C.-H. Angew. Chem., Int. Ed. 2002, 41, 4087-4090. Pentenyl
glycosides: (e) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B. J. Am. Chem. Soc. 1988, 110, 5583-5584. (f) Fraser-Reid, B.; Wu, Z.;
Udodong, U. E.; Ottosson, H. J. Org. Chem. 1990, 55, 6068-6070. (g)
Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, J. R.; Rao,
C. S.; Roberts, C. Synlett 1992, 927-942. (h) Ley, S. V.; Priepke, H. W.
M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2292-2294. Fluorides: (i)
Baeschlin, D. K.; Green, L. G.; Hahn, M. G.; Hinzen, B.; Ince, S. J.; Ley,
S. V. Tetrahedron: Asymmetry 2000, 173-197.
† Both authors contributed equally to this work.
(1) Carbohydrates in Chemistry and Biology; Ernst B., Hart, G. W.,
Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vols. 1-4.
(2) (a) Carbohydrates in Chemistry and Biology; Ernst B., Hart, G. W.,
Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, Chapters 2-9. (b)
Jung, K.-H.; Schmidt, R. R. Chem. ReV. 2000, 100, 4423-4442. (c) Davis,
B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137-2160. (d) Garegg, P. J.
AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205. (e) Boons, G.-J.
Tetrahedron 1996, 52, 1095-1121. (f) Schmidt, R. R.; Kinzy, W. AdV.
Carbohydr. Chem. Biochem. 1994, 50, 21-123. (g) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380-1419. (h)
Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
10.1021/ol034312t CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003

thiodonor is selectively activated with a mild thiophilic
promotor and condensed with a relatively unreactive (“dis-
armed”) thioglycoside.5 The resulting thio disaccharide can
then be activated by a more potent promotor in the next
glycosidic coupling step, thus obviating the need for elaborate
protecting group manipulations at the oligosaccharide stage.
With the easy availability of a large variety of thioglycosidic
building blocks, progress in oligosaccharide synthesis em-
ploying thioglycosides is highly dependent on the develop-
ment of new thiophilic promotor systems. Thus far, relatively
few efficient activation systems for disarmed thioglycosidic
donors have been reported.6
Recently, a breakthrough in the development of novel
thiophilic promotor systems was reported by Crich et al.,6a
who showed that reaction of S-(4-methoxyphenyl)benzene-
thiosulfinate (MBPT, 1a, Scheme 1) and trifluoromethane-
Figure 1. Glycosyl donors (3-5) and acceptors (6-8) employed
in the Ph2SO/Tf2O mediated couplings.
function in 3a by the more nucleophilic thio(p-methoxyphe-
nyl) group in 3b. MBPT/Tf2O (2a)-mediated condensations
of thiomannoside 3b led to the isolation of a variety of
disaccharides in high yield and stereoselectivity.9 In the
course of these studies, we also explored the application of
the more potent thiophilic promotor system BSP/Tf2O (2b)
in the condensation reactions of phenylthioglycosides. To
our surprise, this promotor system also proved to be unable
to activate mannosazide 3a.10 Even more intriguing, the use
of other disarmed donors such as glucosazide 4 and rham-
nosides 5a/b also did not result in productive BSP/Tf2O (2b)-
mediated glycosylations.
Scheme 1. Activated Sulfonium Species 2a-c, Generated by
Reaction of 1a-c with Triflic Anhydride
sulfonic anhydride (Tf2O) results in sulfonium species 2a,
which was capable of promoting the notoriously difficult
formation of a â-mannosidic linkage in excellent yield and
stereoselectivity. The latter activation procedure could be
improved by using the easily accessible 1-benzenesulfinyl
piperidine (BSP, 1b)/Tf2O system, which, in contrast to 1a/
Tf2O, can also be used for the activation of disarmed
thioglycosides.6b,7
As part of a program aimed at the development of efficient
synthetic strategies toward biologically important oligosac-
charides,8 we investigated the applicability of 1a/b in
combination with Tf2O as promotors in the stereoselective
construction of â-mannosamine linkages. We observed that
activating agent 2a failed to effectuate the condensation of
S-phenyl-2-azido-3-O-benzyl-4,6-di-O-benzylidene thioman-
noside (3a, Figure 1) with a variety of acceptors.9 We could
circumvent this limitation by replacing the thiophenyl
Gin et al. recently reported an innovative dehydrative
glycosylation strategy,11 based on the powerful electrophile
diphenylsulfide bis(trifluoromethanesulfonate) (2c), generated
in situ from diphenyl sulfoxide (1c) and Tf2O. It occurred
to us that 2c, which lacks the nitrogen lone pair stabilization
of 2b, would be a stronger electrophile capable of activating
not only anomeric hydroxyl groups but also the weakly
nucleophilic thiofunction present in disarmed thioglycosides.
The Ph2SO/Tf2O (2c) promotor system was evaluated
using the above-mentioned disarmed donor phenyl thiogly-
cosides 3a, 4, and 5a/b and acceptors 6-8 (Figure 1). Indeed
phenyl thiomannoside 3a was readily activated with diphe-
nylsulfide bis(triflate) at low temperatures (-60 °C) and
condensed with acceptors 6-8 to give disaccharides 9-11,
respectively, in excellent yields (Table 1, entries 1-3).
Condensations of 3a with the relatively unreactive acetylated
glucoside 6 as well as its more reactive benzylated congener
7 both occurred with comparable â-selectivity. The more
stereocongested acceptor 8 was condensed with 3a in equal
efficiency, but with a lower stereoselectivity, as compared
to 6 and 7. Interestingly, smooth activation and glycosidation
(5) (a) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett.
2003, 5, 455-458. (b) Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201-
4203. (c) Fridman, M.; Solomon, D.; Yogev, S.; Baasov, T. Org. Lett. 2002,
4, 281-283. (d) Veeneman, G. H.; Van Boom, J. H. Tetrahedron Lett.
1990, 31, 275-278. See also ref 4b-d.
(6) (a) Crich, D.; Smith, M. Org. Lett. 2000, 2, 4067-4069. (b) Crich,
D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020. (c) Kartha, K. P.
R.; Aloui, M.; Field, R. A. Tetrahedron Lett. 1996, 37, 5175-5178. (d)
Ercegovic, T.; Meijer, A.; Magnusson, G.; Ellervik, U. Org. Lett. 2001, 3,
913-915.
(7) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867-8869.
(8) (a) Code´e, J. D. C.; Van der Marel, G. A.; Van Boeckel, C. A. A.;
Van Boom, J. H. Eur. J. Org. Chem. 2002, 3954-3965. (b) Kamst, E.;
Zegelaar-Jaarsveld, K.; Van der Marel, G. A.; Van Boom, J. H.; Lugtenberg,
B. J. J.; Spaink, H. P. Carbohydr. Res. 1999, 321, 176-189. (c) Duynstee,
H.; De Koning, M. C.; Van der Marel, G. A.; Van Boom, J. H. Tetrahedron
Lett. 1998, 39, 4129-4132. (d) Timmers, C. M.; Wighert, S. C. M.;
Leeuwenburgh, M. A.; Van der Marel, G. A.; Van boom, J. H. Eur. J.
Org. Chem. 1998, 1, 91-97.
(9) Litjens, R. E. J. N.; Leeuwenburgh, M. A.; Van der Marel, G. A.;
Van Boom, J. H. Tetrahedron Lett. 2001, 42, 8693-8696.
(10) BSP/Tf2O-mediated glycosylations of the more nucleophilic 3b
proceeded uneventfully and with yields and R/â ratios comparable to those
of the MBPT/TF2O system.
(11) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597-7598. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000,
122, 4269-4279. (c) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem.,
Int. Ed. 2001, 40, 414-417.
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Org. Lett., Vol. 5, No. 9, 2003

promoted coupling of rhamnosides 5a and 5b with 6 (entries
7, 8) proceeded in high yield and expected R-selectivity.14
As the next research objective, we employed the thus
established difference in reactivity between the BSP/Tf2O
and Ph2SO/Tf2O reagents in the development of a novel
chemoselective oligosaccharide synthesis strategy. As a first
example, the construction of trisaccharide 20 was undertaken
(Scheme 2). The armed thiogalactose donor 17 was activated
Table 1. Results of Ph2SO/Tf2O-Mediated Glycosylations
Scheme 2. Chemoselective Glycosylationa
a Key: (a) BSP, Tf2O, TTBP, DCM, (EtO)3P quench, 73%; (b)
Ph2SO, Tf2O, TTBP, DCM, 64%.
by BSP/Tf2O and condensed with disarmed thiomannosazide
18. Unfortunately, although we initially observed the forma-
tion of the expected condensation product, deterioration of
dimer 19 occurred. Apparently, the transiently formed
S-thiophenyl species 2115 activates the dimer thioglycoside
19 resulting in hydrolysis during aqueous workup. On the
basis of this assumption, we reasoned that the timely addition
of a suitable reagent capable of quenching 21 would lead to
more effective glycosylation. Indeed, addition of triethyl
phosphite16 prior to the aqueous workup led to the isolation
of the desired R-linked disaccharide 19 in 74% yield.
Activation of 19 by Ph2SO/Tf2O and condensation with
glucose acceptor 6 proceeded uneventfully, and with excel-
lent stereoselectivity, to provide trisaccharide 20 in 64%
yield.
a Anomeric ratio determined from an anomeric mixture by 1H NMR
analysis.
also occurred readily in the glucosazide series (entries 4-6).
However, a striking difference in stereochemistry of the
newly introduced glycosidic bond in disaccharides 12/14 and
13 was observed. Thus, condensation of glucosazide 4 and
glucoside 6 or 8 gave the R-linked disaccharides (i.e., 12
and 14 in entry 4 and 6, respectively) predominantly, while
condensation of donor 4 and acceptor 7 proceeded with a
high degree of â-selectivity (13, entry 5).12 These results
agree with the finding that the nature of the protecting groups
in the acceptor can have a profound effect on the stereo-
chemical outcome of a glycosylation.13 The Ph2SO/Tf2O-
The potency of the Ph2SO/Tf2O activator system was next
demonstrated in the assembly of trisaccharide 25 (Scheme
3). Activation of disarmed galactose 22 with BSP/Tf2O
(13) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-224.
(b) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-235.
(14) In contrast to 5a/b, phenyl 2,3-O-carbonyl-4-O-(tert-butyldimeth-
ylsilyl)-1-thio-R-L-rhamnopyranoside could be activated by the BSP/Tf2O
system, suggesting that the silyl protecting group has an arming effect on
the thioglycoside: Crich, D.; Li, H. J. Org. Chem. 2001, 67, 4640-4646.
(15) Tentative triflate species 21 was independently generated by
treatment of 1b with 1.0 equiv of thiophenol. Addition of phenyl
thioglycosides (e.g., mannosazide 3a) to this reaction mixture led at higher
temperatures (∼0 °C) to decomposition of the donor glycosides.
(16) Sliedregt, L. A. J. M.; Van der Marel, G. A.; Van Boom, J. H.
Tetrahedron Lett. 1994, 35, 4015-4018.
(12) This unprecedented â-selectivity can be explained by the rapid direct
SN2-like displacement of the intermediate R-triflate, which has also been
observed when MeOH was used as acceptor: Crich, D.; Cai, W. J. Org.
Chem. 1999, 64, 4926-4930.
Org. Lett., Vol. 5, No. 9, 2003
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activation of 24 and condensation with methylglucoside 7
furnished the â-linked trimer 23 (61%).
Scheme 3. Chemoselective Glycosylationa
In conclusion, we have demonstrated Ph2SO/Tf2O to be a
powerful thiophilic promotor system capable of activating
disarmed thioglycosides. In exploiting the difference in
reactivity of the BSP/Tf2O and Ph2SO/Tf2O activating agents,
we have developed a novel chemoselective condensation
sequence in which both armed and disarmed thiodonors can
be chemoselectively condensed in the first glycosylation step.
Research is currently underway to evaluate the scope and
limitations of both reagents in chemoselective condensations
using different thiodonors (for instance, p-methoxyphenyl
and phenyl thioglycosides) and 1-hydroxyl glycosyl donors.
Acknowledgment. We thank the Council for Chemical
Sciences of the Netherlands Organization for Scientific
Research (CW-NWO), the Netherlands Technology Founda-
tion (STW), and Organon N.V. for financial support.
a Key: (a) BSP, Tf2O, TTBP, DCM, (EtO)3P quench, 64%; (b)
Ph2SO, Tf2O, TTBP, DCM, 61%.
Supporting Information Available: General coupling
procedures and characterizations of 9-16, 19, 20, 24, and
25. This material is available free of charge via the Internet
at http://pubs.acs.org.
followed by treatment with thioglycoside 23 and quenching
with (EtO)3P afforded dimer 24 in an efficient chemoselective
glycosylation process. Subsequent Ph2SO/Tf2O-mediated
OL034312T
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Org. Lett., Vol. 5, No. 9, 2003