C-glycosides of 2-amino-2-deoxy sugars. β-C-glycosides and 1,1-disubstituted variants

Article abstract of DOI:10.1021/ol0491540

(Equation Presented) C(1)-Substituted anomeric selenides, derived from azidoselenation of C(1)-methylated glycals, provide access to anomeric radical reactivity that has been used to generate β-C-glycosides and 1,1-disubstituted C-glycosides based on gala

Full text of DOI:10.1021/ol0491540

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2445-2448
C-Glycosides of 2-Amino-2-deoxy
Sugars. â-C-Glycosides and
1,1-Disubstituted Variants
Yan Liu and Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, UK
t.gallagher@bristol.ac.uk
Received May 10, 2004
ABSTRACT
C(1)-Substituted anomeric selenides, derived from azidoselenation of C(1)-methylated glycals, provide access to anomeric radical reactivity
that has been used to generate â-C-glycosides and 1,1-disubstituted C-glycosides based on galacto, gluco, and manno variants of N-acetyl-
2-amino sugars.
N-Acetyl-2-amino-2-deoxy sugars play an integral role in
the structure and function of both O- and N-glycopeptides.1
As a result, the corresponding C-glycosides2 of these im-
portant carbohydrate units represent a potentially valuable
set of molecular tools with which to probe the various roles
played by complex glycoconjugates, and a number of
methods now exist for the synthesis of both R- and â-C-
glycoside variants of 2-amino-2-deoxy sugars exemplified
by 1 and 2 respectively.3 We recently described two com-
Although this chemistry complements other methods3 for
generating R-C-glycosides of 2-amino-2-deoxysugars, we
were interested in exploring related reaction pathways to
provide other less available C-glycoside variations of 2-ami-
no sugars. In this paper we describe anomeric radical
reactivity that provides (i) an alternative entry to â-C-
glycosides of 2-amino-2-deoxy sugars 2 and (ii) disubstituted
C-glycoside derivatives 3.
(2) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. Postema, M.
C-Glycoside Synthesis; CRC Press: Boca Raton, 1995. Levy, D.; Tang, C.
The Chemistry of C-Glycosides; Pergamon: Oxford, 1995. Togo, H.; He,
W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700-717. Skrydstrup, T.;
Vauzeilles, B.; Beau, J.-M. In Carbohydrates in Chemistry and Biology.
The Chemistry of Saccharides; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-
VCH: New York, 2000; Vol. 1, Chapter 20, pp 495-530.
(3) A comprehensive listing of earlier methods for the synthesis of
C-glycosides related to 2-amino-2-deoxy sugars has been presented.4 For
more recent reports, see: Pachamuthu, K.; Gupta, A.; Das, J.; Schmidt, R.
R.; Vankar, Y. D. Eur. J. Org. Chem. 2002, 1479-1483. Ohnishi, Y.;
Ichikawa, Y. Bioorg. Med. Chem. Lett. 2002, 12, 997-999. Dondoni, A.;
Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67, 4475-4486. McGarvey,
G. J.; Schmidtmann, F. W.; Benedum, T. E.; Kizer, D. E. Tetrahedron
Lett. 2003, 44, 3775-3779. Palmier, S.; Vauzeilles, B.; Beau, J. M. Org.
Bioorg. Chem. 2003, 1, 1097-1098. Gaurat, O.; Xie, J.; Valery, J. M. J.
Carbohydr. Chem. 2003, 22, 645-656. Xie, J. Carbohydr. Res. 2003,
338, 399-406. Miquel, N.; Vignando, S.; Russo, G.; Lay, L. Synlett 2004,
341-343. Wen, X. H.; Hultin, P. G. Tetrahedron Lett. 2004, 45, 1773-
1775.
plementary entries to R-C-glycosides 1 that were based on
on the trapping of an anomeric radical, derived from either
an R- or â-anomeric selenide, with an alkene.4 Importantly,
this chemistry also proved applicable to more complex
substrates providing, for example, disaccharide-based R-C-
glycoside derivatives of N-acetyl lactosamine.
(1) Dwek, R. A. Chem. ReV. 1996, 96, 683-720. Herzner, H.; Reipen,
T.; Schultz, M.; Kunz, H. Chem. ReV. 2000, 100, 4495-4537. For recent
discussions on the synthesis and significance of mucin-like glycoproteins,
see: Marcaurelle, L. A.; Bertozzi, C. R. Glycobiology 2002, 12, 69R-
77R.
(4) SanMartin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.; Gallagher,
T. Org. Lett. 2000, 2, 4051-4054. Grant, L.; Liu, Y.; Walsh, K. E.; Walter,
D. S.; Gallagher, T. Org. Lett. 2002, 4, 4623-4625.
10.1021/ol0491540 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/17/2004

The strategy adopted involves the use of C(1)-substituted
glycals as the key carbohydrate precursors, and there are a
number of elegant methods known for assembling glycals
of this type.5 To establish the viability of this strategy, we
have focused on C(1)-methylated glycals 65a and 7, which
were obtained by lithiation6 and methylation of the corre-
sponding per-O-silylated glucal and galactal derivatives 4
and 5 respectively. The resulting C(1)-methyl glycals (con-
ventional sugar numbering is used throughout this paper)
were desilylated and O-acetylated to provide 6 (80% overall
yield from 4) and 7 (94% overall yield from 5) (Scheme 1).
to the analogous reaction involving tri-O-acetyl-D-glucal
(which lacks the methyl substituent at C(1)) that favors the
gluco adduct.9 Following azide reduction and N-acetylation,
the gluco and manno isomers 9 and 10 (now separable) were
obtained in 21% and 70% overall yields, respectively, and
their reactivity was then evaluated independently.
Azidoselenation of the C(1)-methylated galactal deriv-
ative 7 was significantly more stereoselective though less
efficient, and the N-acetyl 2-amino-2-deoxy-1-methylgalac-
tose derivative 11 was obtained in 30% yield.10 Reduction
and N-acetylation of 11 gave 12 in 90% yield.
Initial studies to define the reactivity of selenides 9, 10,
and 12 focused on simple reduction with the expectation that
trapping of the resulting anomeric radical would occur from
the R face11 and thereby provide an entry to â-C-glycosides
based on 2-amino sugars. In the event, reduction of both 9
and 10 provided the corresponding â-C-glycosides 13 and
14 in reasonable yields (Scheme 3). We did not carry out a
Scheme 1. Synthesis of C(1)-Methyl Glycals
Scheme 3. Generation of â-C-Glycosides
The requisite selenyl and acetamido moieties at C(1) and
C(2), respectively, were then introduced via azidoselenation.7
This involved (i) addition of azide radical to the glycal and
trapping of the intermediate anomeric radical by diphenyl
diselenide, followed by (ii) azide reduction and N-acetylation
(Scheme 2).
Scheme 2. Azidoselenation of C(1)-Methyl Glycals
separate reduction of the galacto adduct 12, but the corre-
sponding reduction product â-C-glycoside 15 was isolated
(5) For general entries to C(1)-substituted glycals, see: (a) Nicolaou,
K. C.; Hwang, C.-K.; Duggan, M. E. J. Chem. Soc., Chem. Commun. 1986,
925-926. (b) Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc., Chem.
Commun. 1986, 926-927. (c) Lesimple, P.; Beau, J. M.; Jaurand, G.; Sinay,
P. Tetrahedron Lett. 1986, 27, 6201-6204. (d) Friesen, R. W.; Loo, R. W.
J. Org. Chem. 1991, 56, 4821-4823. (e) Dubois, E.; Beau, J.-M. Carbohydr.
Res. 1992, 228, 103-120. (f) Friesen, R. W.; Loo, R. W.; Sturino, C. F.
Can. J. Chem. 1994, 72, 1262-1272. (g) Postema, M. H. D.; Calimente,
D. Tetrahedron Lett. 1999, 40, 4755-4759. (h) Lui, L.; Postema, M. H. D.
J. Am. Chem. Soc. 2001, 123, 8602-8603. (i) Postema, M. H. D.; Piper, J.
L. Tetrahedron Lett. 2002, 43, 7095-7099. (j) Postema, M. H. D.; Piper,
J. L. Org. Lett. 2003, 5, 1721-1723. (k) Postema, M. H. D.; Piper, J. L.;
Liu, L.; Shen, J.; Faust, M.; Andreana, P. J. Org. Chem. 2003, 68, 4748-
4754. (l) Potuzak, J. S.; Tan, D. S. Tetrahedron Lett. 2004, 45, 1797-
1801.
(6) The glycal lithiation procedures used have been described previ-
ously: Majumder, U.; Cox, J. M.; Rainier, J. D. Org. Lett. 2003, 5, 913-
916. Ja¨kel, C.; Do¨tz, K. H. J. Organomet. Chem. 2001, 624, 172-185.
(7) Czernecki, S.; Randriamandimby, D. Tetrahedron Lett. 1993, 34,
7915-7916. Czernecki, S.; Ayadi, E.; Randriamandimby, D. J. Org. Chem.
1994, 59, 8256-8260. Santoyo-Gonza´lez, F.; Calvo-Flores, F. G.; Garcia-
Mendoza, P.; Herna´ndez-Mateo, F.; Isac-Garcia, J.; Robles-D´ıaz, R. J. Org.
Chem. 1993, 58, 6122-6125.
Azidoselenation of glucal 6 was, as anticipated on the basis
of earlier studies,8 not especially selective, and adduct 8 was
isolated in 82% yield as an inseparable 1:3 mixture of
epimers at C(2). Interestingly and unexpectedly, this addition
process favored the manno isomer (see below) in contrast
2446
Org. Lett., Vol. 6, No. 14, 2004

as the major product (43%) when we attempted to trap the
anomeric radical derived from 12 with styrene (see Scheme
5). The assignment of â-C-glycosides 13, 14, and 15 was
based on H NMR for which JH(1)-H(2) and JH(2)-H(3) were
diagnostic, and in the case of 14, this assignment was
confirmed by NOE experiments.
a more rigorous assignment of the stereochemical out-
come was demanded, and the structure of 1,1-disubstituted
C-glycosides 16-18 was based on NOE studies, as illustrated
in Figure 1.12
1
3
3
Selenides 9, 10, and 12 also offered an additional op-
portunity as an entry to 1,1-disubstituted C-glycosides
represented by 3. This would require C-Se homolysis to
generate the requisite anomeric radical and trapping of this
species with a suitable alkene, rather than simple reduction.
We anticipated that the new C-C bond would form on the
R face, but a concern was the hindered and potentially
unreactive nature of the intermediate anomeric radical.
However, this did not prove to be a barrier to C-C bond
formation, and our results are presented in Scheme 4.
Figure 1. Stereochemical assignment of C-glycosides 16 and 17
(key NOE are indicated by arrows).
One area of potential application of C-glycosides 1 is as
glycosyltransferase inhibitors to block O-glycopeptide syn-
thesis, and the galacto variant 1 (R′) CH2CH2Ph) has begun
to play a role in this respect.13 It was therefore of interest to
assemble a disubstituted variant of 1, namely, the 1,1-
disubstituted galacto derivative 19.
Scheme 4. Generation of 1,1-Disubstituted C-Glycosides
Exposure of selenide 12 to Bu3SnH in the presence of
styrene (20 equiv) gave the target C-glycoside 19 in 29%
yield (Scheme 5). Although this is a low yield, it must be
Scheme 5. Generation of 1,1-Disubstituted C-Glycosides
Based on Styrene and Keck Allylation
Homolysis of gluco isomer 9 in the presence of tert-butyl
acrylate led to the disubstituted C-glycoside 16 in 79%
isolated yield. Similar transformations were carried out using
the manno and galacto adducts 10 and 12 to provide
C-glycosides 17 (48%) and 18 (50%), respectively.
Although earlier precedent4,14b indicated that C-C bond
formation would occur on the R face of the anomeric center,
appreciated that styrene is not generally an efficient trap for
anomeric radicals4 (electron-deficient alkenes being much
(8) For a discussion of the stereoselectivity of this process and strategies
for enhancing gluco selectivity, see: Seeberger, P. H.; Roehrig, S.; Schell,
P.; Wang, Y.; Christ, W. J. Carbohydr. Res. 2000, 328, 61-69. As far as
we are aware, no study of the azidoselenenation (or related processes) have
been reported for C(1)-substituted glycals.
(12) For 16 and 17, we have also observed a NOE between H(5) and
the CH2 of the C(1) substituent, not shown in Figure 1. Similar diagnostic
NOE observations were made in the case of C-glycoside 18, as well as
C-glycosides 19 and 20 (Scheme 5).
(13) Simple O-glycosides (e.g., 1 (R’) OBn) of 2-amino-2-deoxy sugars
act as competitive inhibitors of the glycosylation of GalNAc in vivo. This
has significant implications for the expression of mucins and the intracellular
trafficking of other glycoproteins. Gouyer, V.; Leteurtre, E.; Zanetta, J. P.;
Lesuffleur, T.; Delannoy, P.; Huet, G. Front. Biosci. 2001, 6, D1235-
D1244. Huet, G.; Gouyer, V.; Delacour, D.; Richet, C.; Zanetta, J. P.;
Delannoy, P.; Degand, P. Biochimie 2003, 85, 323-330. Delacour, D.;
Gouyer, V.; Leteurtre, E.; Ait-Slimane, T.; Drobecq, H.; Lenoir, C.; Moreau-
Hannedouche, O.; Trugnan, G.; Huet, G. J. Biol. Chem. 2003, 278, 37799-
37809.
(9) In the case of adduct 10, a NOESY experiment linking the C(1)
methyl group and the NH moiety supported the structure shown in Scheme
2, i.e., R-SePh. The anomeric configurations of 9 and 12 have not been
rigorously determined, but this is not likely to be significant in terms of
the generation and reactivity of the corresponding anomeric radical.4
(10) Azide radical addition to 7 has not yet been optimized but also gave,
after azide reduction and N-acetylation, trace amounts of the talo isomer
1
[axial NHAc at C(2)], which was assigned on the basis of H NMR.
(11) For leading references to the stereoselective reduction of anomeric
radicals, see: Crich, D.; Lim, L. B. L. J. Chem. Soc., Perkin Trans. 1 1991,
2205-2208. Schmid, W.; Christian, R.; Zbiral, E. Tetrahedron Lett. 1988,
29, 3643-3646. Baumberger, F.; Vasella, A. HelV. Chim. Acta 1983, 66,
2210-2222.
(14) (a) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829-
5831. (b) Cui, J. R.; Horton, D. Carbohydr. Res. 1998, 309, 319-330.
Org. Lett., Vol. 6, No. 14, 2004
2447

more effective in this regard), and this case is likely
compounded by the more hindered nature of the intermediate
anomeric radical derived from 12. That this was a slow
process in terms of C-C bond formation was supported by
the observation that the reduction product 15 (see also
Scheme 3) was the major compound isolated from this
reaction.
precursors to C-glycosides via C-Se homolysis and alkene
trapping. Further, this chemistry provides access to a novel
subclass of C-glycoside derivatives, namely, the disubstituted
2-acetamido variants exemplified by 16-20, and we now
plan to extend this strategy to a broader range of C(1)-
substituted glycals.
Finally, C-allylation of selenide 10 under Keck allylation
conditions14 proceeded smoothly to provide C-glycoside 20
in 51% yield (Scheme 5). The introduction of an allyl moiety
is significant in terms of the functionality associated with
the C-glycoside component, and this and related adducts are
currently being exploited to provide access to novel carbo-
hydrate-based tools.
In summary, we have validated a new entry to â-C-
glycosides of N-acetyl-2-amino-2-deoxy sugars. This is based
on extending the synthetic utility of anomeric selenides as
Acknowledgment. We thank EPSRC (Grant GR/R46601)
and acknowledge the support provided by the EPSRC Mass
Spectrometry Service Centre at the University of Swansea.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0491540
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