Stereoselective, electrophilic α- C-sialidation

Article abstract of DOI:10.1021/ol300255q

5-N-Acetyl-5-N,4-O-oxazolidinone protected α- and β-sialyl phosphates react with allyltributylstannane and a variety of trimethylsilyl enol ethers to give α-sialyl C-glycosides in high yield and excellent selectivity. Elimination to give the 2,3-glycal is

Full text of DOI:10.1021/ol300255q

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1342–1345
Stereoselective, Electrophilic
r-C-Sialidation
Amandine Noel,† Bernard Delpech,† and David Crich*,†,‡
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1
Avenue de la Terrasse, 91190 Gif-sur-Yvette, France, and Department of Chemistry,
Wayne State University, Detroit, Michigan 48202, United States
dcrich@chem.wayne.edu
Received January 31, 2012
ABSTRACT
5-N-Acetyl-5-N,4-O-oxazolidinone protected R- and β-sialyl phosphates react with allyltributylstannane and a variety of trimethylsilyl enol ethers to give
R-sialyl C-glycosides in high yield and excellent selectivity. Elimination to give the 2,3-glycal is minimized by the presence of the oxazolidinone ring. The
oxazolidinone ring can be subsequently cleaved under mild conditions at room temperature leaving in place the native acetamide group.
Because of resistance to hydrolytic enzymes and their
ability to mimic native O-glycosides, the C-glycosides have
enjoyed considerable attention from synthetic and medic-
inal chemists.1 One of the earliest,2 most reliable, and
widely applied approaches to C-glycosides has been the
reaction of electrophilic glycosyl donors, typically under
Lewis acid catalysis with C-nucleophiles such as alkenes,
silyl enol ethers, and allylsilanes. Interestingly, however,
following Paulsen’s report that treatment of chloride 1
with allyltrimethylsilane in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) leads exclusively to
the elimination product 3 (Scheme 1),3 this method has not
been applied in the sialic and ulosonic acid series with the
exception of the low yield formation of a C-aryl glycoside 4
from the anomeric acetate 2 (Scheme 1).4
The formation of C-sialosides by the trapping of anome-
ric radicals generated from 1 and related radical precursors
avoids the problem of elimination but is typically un-
selective.3,5 This being the case, sialic and ulosonic acid
C-glycosides are typically generated by alkylation of en-
olate anions or their equivalents, most commonly gener-
ated reductively from thioglycosides or the corresponding
sulfones, when excellent R-selectivity is observed.1c,e,g,6
† CNRS.
‡ Wayne State University.
(1) (a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Pergamon: Oxford, 1995. (b) C-Glycoside Synthesis; Postema, M. H. D., Ed.;
CRC: Boca Raton, FL, 1995. (c) Yuan, X. J.; Linhardt, R. J. Curr. Top. Med.
Chem. 2005, 5, 1393–1430. (d) Du, Y.; Linhardt, R. J. Tetrahedron 1998,
54, 9913–9959. (e) Beau, J.-M.; Gallagher, T. Top. Curr. Chem. 1997,
187, 1–54. (f) Nicotra, F. Top. Curr. Chem. 1997, 187, 55–83. (g) Somsak,
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Beau, J.-M. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart,
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530. (i) Beau, J.-M.; Vauzeilles, B.; Skrydstrup, T. In Glycoscience;
Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 3,
pp 2679À2724. (j) Gyorgydeak, Z.; Pelyvas, I. F. In Glycoscience; Fraser-
Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 1,
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r
10.1021/ol300255q
Published on Web 02/15/2012
2012 American Chemical Society

1-benzenesulfinyl piperidine12 and diphenyl sulfoxide13
with trifluoromethanesulfonic anhydride, and the N-iodo-
succinimideÀtrifluoromethanesulfonic acid pair14 were
unsatisfactory owing to competing reaction with the nucleo-
phile. We turned, therefore, to the phosphates 8 that are
activated under standard Lewis acidic conditions compatible
with electron-rich olefins. Screening experiments revealed
TMSOTf to be a suitable Lewis acid capable of promoting
the reaction of 8with allyltrimethylsilane at À78 °C in dichloro-
methane. These conditions were therefore adopted as standard
and applied to a range of allylmetals and silyl enol ethers as
reported in Table 1. In addition to the use of dichloromethane as
solvent, and in view of the strong R-directing effect exerted in
sialidations in general by the use of acetonitrile-containing
solvents, we also studied the use of a 2:1 mixture of dichloro-
methane and acetonitrile as solvent (Table 1).
Scheme 1. Attempted Electrophilic C-Sialylation
With allyltrimethylsilane as a nucleophile (Table 1, en-
tries 1 and 2), the allyl C-glycosides 10 were obtained in
moderate togood yields, butpoorselectivity irrespectiveof
the solvent employed. With the more nucleophilic allyltri-
butylstannane, 10 was obtained in high yield from the R-
anomer of the sialyl phosphate 8r (Table 1, entry 3), but
only a moderate yield was obtained from the β-anomer 8β
(Table 1, entry 4) irrespective of the solvent employed. The
selectivity for the formation of 10 was essentially complete
when allyltributylstannane was used as the nucleophile,
with only the R-anomer being formed, unimpacted by the
configuration of the donor employed and either of the
solvents studied (Table 1, entries 3 and 4). The stereochem-
istry of the two anomers of the C-allyl sialoside was as-
signed on the basis of NOE correlations between the allylic
methylene group and the axial hydrogensat C4and 6 in the
β-anomer and between the allylic methylene group and the
axial hydrogen at C3 for the R-anomer. The stereochem-
istry of all subsequent C-sialosides was assigned an-
alogously as described in the Supporting Information.
Turning to the use of silyl enol ethers as nucleophiles, the
application of trimethylsiloxyethene gave the C-sialo-
side 11 in high yield and exquisite R-selectivity both in
dichloromethane and in the mixture with acetonitrile
(Table 1, entries 5 and 6). A lower yield was, however,
observed when the β-phosphate 8β was employed as the
donor in dichloromethane. With the trimethylsilyl enol ether
derived from pinacolone (Table 1, entries 7 and 8), the yields
were generally good, irrespective of the configuration of the
donor, and the selectivities were high and in favor of the
R-anomer in dichloromethane. However, interestingly, a
much lower selectivity was noted when the combination
of dichloromethane and acetonitrile was the solvent. With
acetophenone trimethylsilyl enol ether, good yields and
excellent R-selectivities also were obtained from either
anomer of the donor (Table 1, entries 9 and 10). Finally, with
In our laboratory, we have developed the N-acetylox-
azolidinone protected thioglycosides 5 and 6 as highly R-
selective donors for the synthesis of O-sialosides,7 while
closely related oxazolidinones lacking the N-acetyl group
have been developed and employed by the Takahashi,8 De
Meo,9 and other groups.10 Subsequently, Wong and co-
workers converted the thioglycoside 7 to the anomeric
phosphates 8 and showed that they are also excellent R-
sialoside donors.11 We now describe the use of this class of
compounds as highly R-selective electrophilic C-sialosyl
donors, thereby opening up the electrophilic manifold as a
facile route into the sialic acid C-glycosides.
Initial experiments employing 6 and standard thiogly-
coside activating systems such as the combinations of
(7) (a) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387–2391. (b) Crich,
D.; Li, W. J. Org. Chem. 2007, 72, 7794–7797. (c) Crich, D.; Wu, B. Org.
Lett. 2008, 10, 4033–4035. (d) Crich, D.; Navuluri, C. Angew. Chem., Int.
Ed. 2010, 49, 3049–3052. (e) Sun, B.; Jiang, H. Tetrahedron Lett. 2011,
52, 6035–6038. (f) Wang, Y.-J.; Jia, J.; Gu, Z.-Y.; Liang, F.-F.; Li, R.-C.;
Huang, M.-H.; Xu, C.-S.; Zhang, J.-X.; Men, Y.; Xing, G.-W. Carbo-
hydr. Res. 2011, 346, 1271–1276.
(8) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006,
128, 7124–7125.
(9) (a) Farris, M. D.; De Meo, C. Tetrahedron Lett. 2007, 48, 1225–
1227. (b) Harris, B. N.; Patel, P. P.; Gobble, C. P.; Stark, M. J.; De Meo,
C. Eur. J. Org. Chem. 2011, 4023–4027.
(10) (a) Hanashima, S.; K., S.; Ito, Y.; Yamaguchi, Y. Eur. J. Org.
Chem. 2009, 4215–4220. (b) Liang, F.-F.; Chen, L.; Xing, G.-W. Synlett
2009, 425–428. (c) Hanashima, S. Trends Glycosci. Glycobiol. 2011, 23,
111–121.
(12) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–9020.
ꢀ
(13) Codee, 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 2004, 60, 1057–1064.
(14) (a) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331–1334. (b) Konradsson, P.; Udodong,
U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313–4316.
(11) Hsu, C.-H.; Chu, K.-C.; Lin, Y.-S.; Han, J.-L.; Peng, Y.-S.; Ren,
C.-T.; Wu, C.-Y.; Wong, C.-H. Chem.;Eur. J. 2010, 16, 1754–1760.
Org. Lett., Vol. 14, No. 5, 2012
1343

Table 1. Electrophilic C-Sialylation and Subsequent Oxazolidinone Cleavage
a Anomeric ratios were determined by integration of the 1H NMR spectra of the crude reaction mixtures.
trimethylsiloxycyclohexene, an excellent yield of a single
diastereomer 14 was obtained from both phosphates 8. This
compound was assigned as the equatorial C-glycoside on the
basis of NOE measurements. The R-configuration adjacent to
the ketone is tentatively assigned on the basis of the open,
antiperiplanar transition state model shown in Figure 1.15
Four of the C-sialosides (10r and 10β, 12 and 13) were
subjected to a deacetylation and concomitant cleavage of
the oxazolidinone ring with sodium methoxide in metha-
nol at room temperature, all in good yields (Table 1, entries
1/2, 3/4, 7/8, and 9/10). Importantly, the spectroscopic
data for the C-sialosides 15 and 16 correlate with those
described earlier in the literature3 for these known sub-
stances and thereby confirm the configurational assign-
ments made on the basis of NOE measurements. The
ability to cleave the oxazolidinone selectively under mild,
practical conditions, leaving in place the acetamide typi-
cally found in the sialic acid glycosides, is one advantage
presented by the N-acetyloxazolidinone protected donors
5À8, as compared with the N-deacetyl analogs studied by
Figure 1. Proposed transition state for the formation of 14.
(15) Gennari, C. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 629À660.
1344
Org. Lett., Vol. 14, No. 5, 2012

Takahashi and De Meo,8,9 which require much harsher
conditions for removal of the oxazolidinone ring, followed
by N-acetylation.
O-glycosides.16 In particular, its ability to direct electro-
philic C- and O-glycosylation to the formation of equatorial
glycosides is remarkable and closely resembles the parallel
effect of the benzylidene acetal in mannopyranosylation.17
While the underlying reasons for this selectivity are not
yet entirely clear, we maintain that they are related to a
combination of the restriction of conformational mobi-
lity imposed by the trans-fused oxazolidinone ring
and its powerful electron-withdrawing effect due the co-
planarity of the carbonyl dipole with the mean plane of the
pyranose ring.18
Overall, the use of the 5-N,4-O-oxazolidinone protecting
group adds the stereoselective electrophilic C-glycosyla-
tion route to the existing methods for the formation of the
sialic acid C-glycosides and, in doing so, opens up a new
avenue for the synthesis of glycomimetics. Furthermore,
the 5-N,4-O-protecting group for the sialic acid donors joins
the 4,6-O-benzylidene acetal group in the hexopyranoside
class of donors in displaying an apparent commonality
of mechanism for the formation of both the C- and
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153. (b) Aubry, S.;
Sasaki, K.; Sharma, I.; Crich, D. Top. Curr. Chem. 2011, 301, 141–188.
(17) (a) Crich, D.; Sharma, I. Org. Lett. 2008, 10, 4731–4734.
(b) McGarvey, G. J.; LeClair, C. A.; Schmidtmann, B. A. Org. Lett.
2008, 10, 4727–4730.
(18) Crich, D. J. Org. Chem. 2011, 76, 9193–9209.
The authors declare no competing financial interest.
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