Thioglycosides protected as trans-2,3-cyclic carbonates in chemoselective glycosylations

Article abstract of DOI:10.1021/ol016869j

(Matrix Presented) Thioglycosides protected as trans-2,3-cyclic carbonates have significantly lower anomeric reactivities than fully acylated and N-acyl-protected thioglycosides and can be used as acceptors in chemoselective glycosylations with a wide ran

Full text of DOI:10.1021/ol016869j

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4201-4203
Thioglycosides Protected as
Trans-2,3-Cyclic Carbonates in
Chemoselective Glycosylations
Tong Zhu and Geert-Jan Boons*
Complex Carbohydrate Research Center, The UniVersity of Georgia,
220 RiVerbend Road, Athens, Georgia 30602
gjboons@ccrc.uga.edu
Received October 5, 2001
ABSTRACT
Thioglycosides protected as trans-2,3-cyclic carbonates have significantly lower anomeric reactivities than fully acylated and N-acyl-protected
thioglycosides and can be used as acceptors in chemoselective glycosylations with a wide range of thioglycosyl donors. The resulting
thioglycosides can be further activated to give 1,2-cis-linked glycosides.
Chemoselective glycosylations allow the rapid assembly of
complex oligosaccharides without protecting group manipu-
lations.1 In a typical procedure, an activated (armed) thio-
glycoside, which bears an electron-donating protecting group
(e.g., ether) at C-2, is coupled in a chemoselective manner
with a less reactive thioglycoside (disarmed) usually having
an electron-withdrawing ester protecting group at C-2.2 Next,
the anomeric center of the resulting disaccharide can be
activated with a more powerful promoter and reaction with
a suitable acceptor will yield a trisaccharide. The chemo-
selective assembly of more complex oligosaccharides re-
quires a wider range of saccharide building blocks of
different anomeric reactivity, and in this respect, Ley and
co-workers were the first to show that thioglycosides, bearing
a dispiroketal (dispoke) or cyclohexane-1,2-diacetal (CDA)
protecting group, have reactivities between armed and
disarmed thioglycosides.3 Wong and co-workers have sys-
tematically examined the relative reactivity of a large number
of p-methylphenyl thioglycosides, and this information was
used to develop a computerized program for the design of
synthetic schemes for “one-pot multistep” chemoselective
assemblies of complex oligosaccharides.4
It is important to note that apart from thioglycosides,
pentenyl glycosides,5 glycals,6 glycosyl fluorides,7 and phos-
phoroamidate8 have been employed in chemoselective gly-
cosylations, however, fewer levels of anomeric reactivity
have been described for these derivatives.
Thioglycosides of low anomeric reactivity usually have
electron-withdrawing ester groups at the C-2 position, and
this feature imposes serious limitations for chemoselective
glycosylations. This type of functionality will perform
neighboring group participation during glycosylations leading
(3) (a) Boons, G.-J.; Grice, P.; Leslie, R.; Ley, S. V.; Yeung, L. L.
Tetrahedron Lett. 1993, 34, 8523. (b) Grice, P.; Ley, S. V.; Pietruszka, J.;
Priepke, H. W. M.; Warriner, S. L. J. Chem. Soc., Perkin Trans. 1 1997,
351. (c) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51.
(4) Zhang, Z.; Ollmann, I. R.; Ye, X.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734.
(5) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, J.
R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927.
(6) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6656.
(1) For a review on strategies in oligosaccharides synthesis, see: Boons,
G.-J. Tetrahedron 1996, 52, 1095.
(2) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275.
(7) Barrena, M. I.; Echarri, R.; Castillon, S. Synlett 1996, 675.
(8) Hashimoto, S.; Sakamoto, H.; Honda, T.; Abe, H.; Nakamura, S.;
Ikegami, S. Tetrahedron Lett. 1997, 38, 8969.
10.1021/ol016869j CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/28/2001

to the stereospecific formation of 1,2-trans glycosides and
as a result, 1,2-cis glycosides cannot be introduced at a final
stage of a chemoselective glycosylation sequence. To address
this problem, we have developed a strategy whereby the
anomeric reactivity of thioglycosides is controlled by the
bulkiness of the anomeric thio group.9 Although this ap-
proach widened the scope of chemoselective glycosylations,
it is still hampered by the fact that the nature of the C-2
protecting group overrides the controlling effect introduced
by leaving groups of different size. It is obvious that there
is a great need for deactivated (disarmed) thioglycosides that
can be used in chemoselective glycosylation and will give
1,2-cis glycosides.
We report here that trans-2,3-cyclic carbonates deactivate
the anomeric center of thioglycosides both electronically and
conformationally,5 and as a result, such derivatives are
significantly less reactive than corresponding thioglycosides
that have ester-protecting groups at C-2. Importantly, it was
anticipated that trans-2,3-cyclic carbonates cannot perform
neighboring group participation during glycosylations and,
therefore, under appropriate conditions should give R-gly-
cosides as the major product.10
N-iodosuccinimide (NIS) and trimethylsilyl trifluoromethane-
sulfonate (TMSOTf)12 mediated coupling of 3 with 4 gave
disaccharide 5 in a yield of 64%. MALDI-TOF analysis of
the crude reaction mixture indicated that no self-condensation
or oligomerization of 3 had occurred. Furthermore, only the
â-anomer was formed due to neighboring group participation
by the Lev ester at C-2 of 4. Additional experiments showed
that thioglycoside 3 remains intact upon treatment with the
following promoters of thioglycosides: NIS/TMSOTf, NIS/
AgOTf,12a MeOTf13 (in dichloromethane at room tempera-
ture). This finding prompted us to employ the highly
deactivated donors 6, 8, and 10, which can be activated with
these promoters. Indeed, coupling of the fully benzoylated
thioglucoside 6 with cyclic carbonate 3 in the presence of
NIS/TMSOTf afforded disaccharide 7 in 72% yield. In a
similar manner, disaccharide 9 was obtained in an excellent
yield of 81% using the fully benzoylated thiogalactoside 8.
In both reactions, complete chemoselectivity was achieved
and only â-glycosides were formed. Remarkably, the un-
reactive N-phthalimido derivative 10 was selectively acti-
vated by NIS/TMSOTf and reaction with 3 provided
disaccharide 11 in 47% yield (Scheme 2). The results of these
To explore the potential of trans-2,3-cyclic carbonates,
compound 3 was prepared and its glycosyl accepting property
was examined. Thus, treatment of thioglycoside 1 with
phosgene in the presence of triethylamine as an acid
scavenger gave 2 as crystalline material in a quantitative
yield. Regioselective opening of the benzylidene acetal using
sodium cyanoborohydride and hydrogen chloride in tetra-
hydrofuran provided the desired glycosyl acceptor 3 bearing
a free hydroxyl at C-4 (Scheme 1).11
Scheme 2a
Scheme 1a
a Key: (a) phosgene (1.9 M solution in toluene), Et3N, DCM,
100%; (b) NaCNBH3, HCl/Et2O, MS 3 Å, THF, 62%.
With thioglycoside 3 in hand, attention was focused on
chemoselective glycosylations. In first instance, the electroni-
cally deactivated thioglycoside 4 was chosen as the glycosyl
donor to investigate the relative reactivity of 3. As expected,
a Key: (a) NIS, TMSOTf, MS 4 Å, DCM, 0 °C; (b) NIS,
TMSOTf, MS 4 Å, DCM, rt.
glycosylations demonstrate that the anomeric reactivity of
thioglycoside 3 is much lower than that of acylated deriva-
tives.
In the next stage of the research, attention was turned to
the use of 2,3-carbonates as glycosyl donors for the synthesis
of R-glycosides and disaccharide 9 was chosen as the
(9) (a) Boons, G.-J.; Geurtsen, R.; Holmes, D. Tetrahedron Lett. 1995,
36, 6325. (b) Geurtsen, R.; Holmes, D. S.; Boons, G.-J. J. Org. Chem.
1997, 62, 8145.
(10) During the preparation of this manuscript, Kerns et al. reported the
use of oxazolidinone protected glucosamine derivatives for the synthesis
of R-linked 2-amino glycosides. Benakli, K.; Zha, C.; Kerns, R. J. J. Am.
Chem. Soc. 2001, 123, 9461. For examples of using 2,3-cyclic carbonates
as glycosyl donors, see: (a) Gorin, P. A.; Perlin, A. S. Can. J. Chem. 1961,
39, 2474. (b) Betaneli, V. I.; Ovchinnikov, M. V.; Backinowsky, L. V.;
Kochetkov, N. K. Carbohydr. Res. 1980, 84, 211. (c) Kochetkov, N. K.;
Torgov, V. I.; Malysheva, N. N.; Shashkov, A. S. Tetrahedron 1980, 36,
1099. (d) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291.
(11) Garegg, P. J.; Hultberg, H.; Wallin, S.; Carbohydr. Res. 1982, 108,
97.
(12) (a) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron
Lett. 1990, 31, 4313. (b) Veeneman, G. H.; van Leeuwen, S. H.; van Boom.
J. H. Tetrahedron Lett. 1990, 31, 1331.
(13) (a) Lo¨nn, H. Carbohydr. Res. 1985, 139, 105. (b) Lo¨nn, H.
Carbohydr. Res. 1985, 139, 115.
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Org. Lett., Vol. 3, No. 26, 2001

glycosyl donor and 1,2:3,4-di-O-isopropylidene-R-D-galac-
tose (12) was used as the model acceptor. As expected, NIS/
TMSOTf or MeOTf failed to activate 9. When dimethyl-
(thiomethyl)sulfonium triflate (DMTST)14 was used as the
promoter, several unidentified products were formed along
with the desired trisaccharide and unreacted starting material.
Fortunately, PhSOTf, which was generated in-situ by the
reaction of PhSCl with AgOTf,15 proved to be the activator
of choice and gave trisaccharide 13 in a yield of 74% as a
mixture of anomers (R/â ) 2/5) when the coupling was
performed in dichloromethane at -78 °C. Interestingly, a
similar yield and stereochemical outcome was obtained when
Crich’s reverse addition protocol16 was adopted. A low
R-selectivity (R/â ) 3/2) was obtained when diethyl ether
was used as the reaction solvent. Fortunately, mainly the
R-glycoside (R/â ) 5/1) was obtained when the reaction was
performed in a mixture of toluene/1,4-dioxane (1/3, v/v)17
at 0 °C albeit in a somewhat lower yield (64%). When
glycosyl acceptor 14, having a secondary hydroxyl was
coupled with 9, using the same activator and solvent mixture,
trisaccharide 15 was formed with highly R-stereoselectivity
in a reasonable yield (R/â ) 8/1, 51%) (Scheme 3).
Scheme 3a
In conclusion, it is demonstrated that thioglycosides
protected as trans-2,3-cyclic carbonates have significantly
lower anomeric reactivities than fully acylated and N-acyl-
protected thioglycosides and as a result these derivatives can
be used as acceptors in chemoselective glycosylations with
a wide range of C-2 alkylated or acylated thioglycosyl
donors. Its synthetic value was further demonstrated by
employing trans-2,3-cyclic carbonate protected thioglycosides
as glycosyl donors and under the appropriate conditions the
substrates provided mainly 1,2-cis-linked glycosides. The use
of trans-2,3-cyclic carbonate protected thioglycosides pro-
vides a new level of anomeric reactivity and therefore widens
the scope of existing chemoselective glycosylation strategies.
In particular, these new substrates make it possible to
synthesize trisaccharides having the 1′′,2′′-trans and 1′,2′-
cis glycosidic linkage sequences.
a Key: (a) PhSCl, AgOTf, DTBMP, MS 4 Å, toluene/1,4-dioxane
(1/3, v/v), 0 °C.
Acknowledgment. We wish to thank the office of vice
president of research of the University of Georgia for
financial support.
Supporting Information Available: Detailed experimen-
tal procedures with spectroscopic data for compounds 2, 3,
5, 7, 9, 11, 13, and 15 as well as the 1H NMR and 13C NMR
spectra of those compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Fugedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, C9.
(15) Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996, 61, 1702.
(16) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
(17) Demchenko, A.; Stauch, T.; Boons, G.-J. Synlett 1997, 818.
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