Galacto, Gluco, Manno, and Disaccharide-Based C-Glycosides of 2-Amino-2-deoxy Sugars

Article abstract of DOI:10.1021/ol0269695

(Matrix Presented) Starting from readily available precursors, selenoglycosides derived from GalNAc, GlcNAc, and ManNAc were prepared by either a one- or a two-step process. The anomeric selenides underwent facile C-Se homolysis to provide the correspondi

Full text of DOI:10.1021/ol0269695

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4623-4625
Galacto, Gluco, Manno, and
Disaccharide-Based C-Glycosides of
2-Amino-2-deoxy Sugars
Laura Grant,† Yan Liu,† Kenneth E. Walsh,† Daryl S. Walter,‡ and
,†
Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, U.K., and Roche
DiscoVery Welwyn, Broadwater Road, Welwyn AL7 3AY, U.K.
t.gallagher@bristol.ac.uk
Received September 26, 2002
ABSTRACT
Starting from readily available precursors, selenoglycosides derived from GalNAc, GlcNAc, and ManNAc were prepared by either a one- or a
two-step process. The anomeric selenides underwent facile C−Se homolysis to provide the corresponding anomeric radicals, which were
trapped with alkenes to give C-glycosides. This provides a general entry to r-C-glycosides based on 2-amino-2-deoxy sugars that is also
applicable to disaccharide variants.
C-Glycosides based on biologically significant carbohydrates
represent potentially useful probes for determining carbo-
hydrate function and regulation.1 2-Amino-2-deoxy sugars
are important components of oligosaccharides and of both
N- and O-glycopeptides,2 and we recently described a
stereochemically efficient entry to R-C-glycosides 4 based
on N-acylgalactosamine (Scheme 1).3 This process offers the
added advantage that the nature of the N-substituent associ-
ated with the C-glycoside 4 can be varied (N-Ac vs N-Boc
vs N-COCF3).
Scheme 1. Azidoselenation as an Entry to R-Selenoglycosides
† University of Bristol.
‡ Roche Discovery. Current address: GlaxoSmithKline, The Frythe,
Welwyn AL6 9AR, U.K.
(1) 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.
(2) For reviews of synthetic studies associated with glycosylation of
2-amino-2-deoxy sugars, see: Banoub, J.; Boullanger, P.; Lafont, D. Chem.
ReV. 1992, 92, 1167-1195. 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. Simple O-
glycosides of 2-amino-2-deoxy sugars can 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 glyco-
proteins: Gouyer, V.; Leteurtre, E.; Zanetta, J. P.; Lesuffleur, T.; Delannoy,
P.; Huet, G. Front. Biosci. 2001, 6, D1235-D1244.
Central to this strategy was the use of an R-selenide 3 as
a stable precursor to the corresponding anomeric radical, and
3 was constructed via 2, the product of azidoselenation of
3,4,6-tri-O-acetyl-D-galactal 1.
(3) SanMartin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.; Gallagher,
T. Org. Lett. 2000, 2, 4051-4054.
10.1021/ol0269695 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/27/2002

The approach shown in Scheme 1 is flexible in terms of
the target C-glycosides,4,5 but the use of azidoselenation6 as
a key step in this sequence has significant limitations.
While this addition process works well for derivatives of
D-galactal (e.g., 1), the use of the corresponding peracetylated
D-glucal leads to a mixture of the D-gluco and D-manno
adducts. The radical addition can be controlled to favor the
gluco adduct,7 but the manno isomer is much less accessible.
Furthermore, disaccharide-based glycals, e.g., D-maltal, are
poor substrates for this radical addition reaction, leading to
very low yields of adducts.8
Scheme 2. One- and Two-Step Selenoglycosylation
Proceduresa
We now report procedures that address these limitations
associated with azidoselenation, and these enable selective
access to â-anomeric selenides based on the galacto and
gluco configurations, as well as the R-anomeric selenide
corresponding to the manno configuration. This selenium-
based method has also been applied to two representative
disaccharides, which also function as substrates for C-
glycoside synthesis.
The solution involves direct synthesis of the anomeric
selenides from the corresponding and readily available 2-N-
acetamido sugars. Two approaches are presented, which are
illustrated in Scheme 2.9
In a two-step protocol, peracetylated N-acetyl-D-glucos-
amine 5 was reacted with TMSOTf or BF3‚Et2O to give
oxazoline 6. Exposure of 6 to PhSeH in the presence of
camphorsulfonic acid (CSA) gave the target â-selenide 7 in
63% overall yield. Alternatively, 7 is available in one
operation and in 92% yield by direct treatment of 5 with
PhSeSiMe3 and TMSOTf. These procedures are applicable
to the galactosamine and mannosamine derivatives starting
from the commercially available peracetylated pyranosides
a Reagents and conditions: (a) TMSOTf, Cl(CH2)2Cl, 50 °C; (b)
PhSeH (2 equiv), CSA (cat.), Cl(CH2)2Cl, reflux; (c) PhSeTMS (2
b
equiv), TMSOTf, Cl(CH2)2Cl, 50 °C. Overall yield for the two-
c
step procedure (via the corresponding oxazoline). Yield for the
one-step procedure.
8 and 10 and provide the corresponding â-selenide 9 (galacto)
and R-selenide 11 (manno), respectively.10
Crucial to the incorporation of this chemistry into the
radical-mediated strategy for C-glycoside synthesis (as
outlined in Scheme 1) was validation of 7, 9, and 11 as
precursors to the corresponding anomeric radicals. In this
sense, it is important to recognize that azidoselenation of
tri-O-acetyl-D-galactal 1 leads (ultimately) to the R-selenide
3, whereas the chemistry outlined in Scheme 2 leads to the
isomeric â-selenide 9. Nevertheless, 9 did undergo smooth
C-Se homolysis, and the resulting radical was trapped
efficiently by either tert-butyl acrylate or styrene to give the
R-C-glycosides 12a3 and 12b3 in 68 and 41% yields,
respectively (Scheme 3).11,12 These products were identical
to those prepared from the corresponding R-selenide 3.
In a similar fashion, the â-gluco selenide 7 and the
R-manno isomer 11 underwent C-Se cleavage and addition
to tert-butyl acrylate and styrene to give the R-C-glycosides
13a and 13b and 14a and 14b, respectively. The stereo-
chemistry of C-glycoside 13a, which adopts a 4C1 conforma-
(4) A comprehensive listing of earlier methods for the synthesis of
C-glycosides related to 2-amino-2-deoxy sugars has been presented earlier.
For more recent reports, see: Rohrig, C. H.; Takhi, M.; Schmidt, R. R.
Synlett 2001, 1170-1172. Yang, G. L.; Franck, R. W.; Bittman, R.;
Samadder, P.; Arthur, G. Org. Lett. 2001, 3, 197-200. Westermann, B.;
Walter, A.; Florke, U.; Altenbach, H. J. Org. Lett. 2001, 3, 1375-1378.
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.
(5) For methods involving the generation and trapping of an anomeric
radical, see: (a) Abel, S.; Linker, T.; Giese, B. Synlett 1991, 171-172. (b)
Czernecki, S.; Ayadi, E.; Xie, J. Tetrahedron Lett. 1996, 37, 9193-9194.
(c) Roe, B. A.; Boojamra, C. G.; Griggs, J. L.; Bertozzi, C. R. J. Org.
Chem. 1996, 61, 6442-6445. (d) Cui, J. R.; Horton, D. Carbohydr. Res.
1998, 309, 319-330. (e) Junker, H. D.; Fessner, W. D. Tetrahedron Lett.
1998, 39, 269-272. (f) Junker, H. D.; Phung, N.; Fessner, W. D.
Tetrahedron Lett. 1999, 40, 7063-7066.
(6) For studies relating to the azidoselenation of glycals, see: Czernecki,
S.; Randriamandimby, D. J. Carbohydr. Chem. 1996, 15, 183-190.
Czernecki, S.; Ayadi, E.; Randriamandimby, D. J. Chem. Soc., Chem.
Commun. 1994, 35-36. Czernecki, S.; Ayadi, E.; Randriamandimby, D. J.
Org. Chem. 1994, 59, 8256-8260. Czernecki, S.; Randriamandimby, D.
Tetrahedron Lett. 1993, 34, 7915-7916. Santoyo-Gonza´lez, F.; Calvo-
Flores, G.; Garc´ıa-Mendoza, P.; Herna´rdez-Mateo, F.; Isac-Garc´ıa, J.;
Robles-D´ıaz, R. J. Org. Chem. 1993, 58, 6122-6125.
(10) The R-anomer of 6 gave 7 in 68% yield using the one-step procedure.
In the two-step protocol, we obtained >95% yields of oxazolines (cf. 6),
but the subsequent ring opening with PhSeH/CSA was less efficient. The
stereochemical assignment of anomeric selenides 7, 9, and 11 is based
(7) Seeberger, P. H.; Roehrig, S.; Schell, P.; Wang, Y.; Christ, W. J.
Carbohydr. Res. 2000, 328, 61-69.
(8) Santoyo-Gonza´lez, F.; Calvo-Flores, G.; Garc´ıa-Mendoza, P.; Her-
na´rdez-Mateo, F.; Isac-Garc´ıa, J.; Robles-D´ıaz, R. Carbohydr. Res. 1994,
260, 319-321.
(9) Selenoglycosides of 2-amino-2-deoxy sugars have found application
in O-glycosylation processes. Mehta, S.; Pinto, B. M. Tetrahedron Lett.
1991, 32, 4435-4438. Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58,
3269-3276. Carriere, D.; Meunier, S. J.; Tropper, F. D.; Cao, S.; Roy, R.
J. Mol. Catal. A-Chem. 2000, 154, 9-22.
1
primarily on H NMR. See the Supporting Information.
(11) â-Anomer 9 was less reactive than R-anomer 3. R-Anomer 3 reacted
at room temperature, using Bu3SnH in PhMe, with Et3B/O2 as initiator,
whereas 9 was unreactive under these conditions. Similar differences were
observed between 7 and the corresponding R-anomer.
(12) Reaction of 7 with tert-butyl acrylate using tris(trimethylsilyl)silane
(TTMS), AIBN, PhH, reflux gave 13a in 93% yield. The same reaction,
but replacing AIBN with Et3B/O2 as initiator, gave 13a in 71% yield.
4624
Org. Lett., Vol. 4, No. 26, 2002

Scheme 3. Synthesis of Galacto-, Gluco-, and Manno-Based
R-C-Glycosidesa
Scheme 4. Disaccharide-Based Selenoglycosides and
Application to C-Glycoside Synthesisa
a Reagents and conditions: (a) H2CdCHCO2-t-Bu or PhCHdCH2
(20 equiv), n-Bu3SnH, AIBN, PhH, reflux.
a Reagents and conditions: (a) TMSOTf, TMSSePh (1.5 equiv),
Cl(CH2)2Cl, rt, 6 days; (b) H2CdCHCO2-t-Bu (20 equiv), n-Bu3SnH,
AIBN, PhH, reflux.
1
3
tion, was established by H NMR: H(2) δ 4.51 (td, J2,3
)
3J2,NH 8.5 Hz, J1,2 3.8 Hz). In the case of C-glycoside 14a,
assignment of the R-configuration of the predominant C1
3
4
In summary, both R- and â-selenoglycosides provide
viable sources of anomeric radical reactivity that are well
suited to the synthesis of C-glycoside analogues of 2-amino-
2-deoxy sugars. Application of “conventional” glycosylation
conditions provides the requisite selenoglycosides (7, 9, 11,
16, and 18) in good yield directly from commercially
available starting materials. Most significantly, the results
reported in this paper extend our earlier work3 by providing
a more general entry to this potentially important class of
C-glycosides.
1
conformer was again made using H NMR: H(2) δ 4.46
(dt, J2,NH ) 8.9 Hz, J1,2 ) J2,3 3.9 Hz).13
3
3
3
The other significant problem associated with azidosel-
enation is the failure of disaccharide-based glycals to undergo
efficient addition,14 which limits the use of azidoselenation
to monosaccharide substrates. However, direct formation of
selenoglycosides from disaccharides is feasible, and is
illustrated in Scheme 4 for hepta-O-acetyl-N-acetyl-D-lac-
tosamine 15.15
The synthesis of the target selenoglycoside 16 was
achieved using the one-step procedure from 15 in 73% yield,
using the conditions developed for the monosaccharide
variants (Scheme 2). The configuration of â-selenide 16 was
Acknowledgment. We thank EPSRC and Roche Dis-
covery for the provision of a CASE award (to K.E.W.) and
EPSRC (Grant No. GR/R46601).
1
3
3
confirmed by H NMR (H(2) dd, J1,2 ) 10 Hz and J2,3
)
9.5 Hz).
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.
tert-Butyl acrylate served as an effective trap for the
anomeric radical derived from 16, and the R-C-glycoside
17 was isolated in 37% yield.16 Similarly, selenoglycoside
18, derived from the peracetylated derivative of disaccharide
â-D-Galp-1f 4-D-ManpNAc,17 underwent C-Se bond ho-
molysis and addition to tert-butyl acrylate to provide R-C-
glycoside 19 in 43% yield.18
OL0269695
(16) On the basis of 1H NMR, the conformation of the gluco ring of 18
3
deviates from the expected 4C1 arrangement: J3,
)
3J2, ) 3.4 Hz.
3
4
Horton5d has observed similar effects for C-glycosides based on GlcNAc,
which exist as an equilibrium between 4C1 and 1C4 conformers. As a
consequence, the stereochemical assignment of 17 remains tentative.
(17) The Heynes rearrangement of lactulose generates a 3: 1 mixture
of N-acetyllactosamine (major component) and the isomeric disaccharide
â-D-Galp-1f 4-D-ManpNAc.15 (This disaccharide is also available from
Dextra Laboratories, Reading, U.K.). Using the “one step” procedure,
selenoglycoside 18 was obtained in 91% yield from hepta-O-acetyl-â-D-
Galp-1f4-D-ManpNAc.
(13) Conventional sugar numbering has been used for simplicity, and
full spectroscopic details are available in the Supporting Information. When
styrene, a less reactive trap, was used, the major byproduct was the
corresponding peracetylated 1,5-anhydro-2-deoxy-D-pyranose.
(14) Santoyo-Gonza´lez et al.8 have reported that azidoselenation of
disaccharide-based glucals is low yielding and slow (1-3 weeks). In our
hands, the adduct derived from peracetylated D-maltal was obtained in <10%
yield after 1 week.
(15) Hepta-O-acetyl-N-acetyl-D-lactosamine 15 was obtained from
lactulose using the Heynes rearrangement. Wrodnigg, T. M.; Stutz, A. E.
Angew. Chem., Int. Ed. 1999, 38, 827-828.
(18) In addition to producing C-glycosides 17 and 19, reaction of both
16 and 18 gave the corresponding 1,5-anhydro-2-deoxy-D-pyranoses, which
were isolated in 44% and 40% yields, respectively.
Org. Lett., Vol. 4, No. 26, 2002
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