Stereoselective synthesis of a C-linked neuraminic acid disaccharide: Potential building block for the synthesis of C-analogues of polysialic acids

Article abstract of DOI:10.1021/jo801946y

(Chemical Equation Presented) C-Linked neuraminic acid disaccharide was synthesized in a diastereoselective manner from a sulfone donor and aldehyde acceptor, which was protected as a propargyl ether, through a samarium-mediated coupling reaction. The resulting disaccharide has acetal and phenyl sulfide functional groups that can be easily converted into aldehyde and phenyl sulfone groups by photolysis and oxidation reactions to serve as disaccharide acceptor and donor, respectively.

Full text of DOI:10.1021/jo801946y

found in embryonic tissues and participates in developmental
biology.6 In this respect, PSAs are important targets for
biological studies, in the development of vaccines for protection
against meningococcal infection, and for the treatment of various
cancers including Wilms’ tumor and small cell lung carcinoma.7,8
Stereoselective Synthesis of a C-Linked
Neuraminic Acid Disaccharide: Potential Building
Block for the Synthesis of C-Analogues of
Polysialic acids
PSAs are known to exhibit both chemical and enzymatic
hydrolytic instability.9 The PSA glycosidic linkages are very
labile and subject to self-cleavage under mildly acidic condi-
tions. In contrast, C-glycosides, in which the interglycosidic
oxygen atoms are replaced with carbon atoms, are resistant to
chemical and enzymatic degradation.10 The unusual lability of
PSAs, their participation in developmental biology, and their
reappearance in various tumors makes their C-glycosidic
analogues ideal targets for a wide array of experimental,
biological, and potential therapeutic applications.11
Jin-Hwan Kim, Fei Huang, Mellisa Ly, and
Robert J. Linhardt*
Department of Chemistry and Chemical Biology, Center for
Biotechnology and Interdisciplinary Studies, Rensselaer
Polytechnic Institute, Troy, New York 12180
linhar@rpi.edu
ReceiVed September 2, 2008
Over the past 10 years, samarium-mediated C-glycosylation
reactions have been reported by our laboratory12 and the Beau
research group13 for the synthesis of C-linked R-sialosides.
Recently, we reported the first synthesis of a C-linked neuramin-
ic acid disaccharide as a versatile precursor of C-analogues of
oligosialic acids and gangliosides.12f However, this synthesis
afforded a 1:1 ratio of R- and S-diastereoisomers at the bridge
hydroxymethylene group, requiring additional steps to remove
this hydroxyl group. The lack of stereoselectivity and the
development of a more efficient strategy for C-oligosialic acids
synthesis prompted us to investigate new protecting groups and
a common donor-acceptor concept, widely used by others in
oligosaccharide synthesis.14 In this effort, we found that
propargyl protecting group chemistry afforded a single diaste-
reoisomer with a photolabile protecting group for sialic acid
aldehyde protection. Furthermore, this protecting group was well
suited for the development of a common donor-acceptor
strategy owing to its easy introduction and removal under mild
reaction conditions.
C-Linked neuraminic acid disaccharide was synthesized in
a diastereoselective manner from a sulfone donor and
aldehyde acceptor, which was protected as a propargyl ether,
through a samarium-mediated coupling reaction. The result-
ing disaccharide has acetal and phenyl sulfide functional
groups that can be easily converted into aldehyde and phenyl
sulfone groups by photolysis and oxidation reactions to serve
as disaccharide acceptor and donor, respectively.
Herein, we report a diastereoselective synthesis of a C-linked
neuraminic acid disaccharide that is useful as a donor-acceptor
disaccharide for the further synthesis of C-linked R(2-8)
Polysialic acid (PSA), a long linear R(2-8)-linked polymer
of sialic acid, is widely distributed in nature, from bacteria to
humans. PSA is expressed on the meningitis-causing bacteria
Neisseria meningitidis B and the capsular polysaccharide of
Escherichia coli K1.1-3 It has also been found on the cell surface
in a number of important cancers and is believed to be associated
with metastasis and correlates with tumor progression.4 PSA is
most often found as an N-linked glycan on neural cell adhesion
molecules (PSA-NCAM) and attenuates NCAM adhesion,
facilitating neural cell migration and regeneration.5 PSA is also
(6) Buttner, B.; Kannicht, C.; Reutter, W.; Horstkorte, R. Biochem. Biophys.
Res. Commun. 2003, 310, 967–971.
(7) Rothbard, J. B.; Brackenbury, R.; Cunningham, B. A.; Edelman, G. M.
J. Biol. Chem. 1982, 257, 11064–11069.
(8) Roth, J.; Zuber, C.; Wagner, P.; Taatjes, D. J.; Weisgerber, C.; Heitz,
P. U.; Goridis, C.; Bitter-Suermann, D. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
2999–3003.
(9) Manzi, A. E.; Higa, H. H.; Diaz, S.; Varki, A. J. Biol. Chem. 1994, 269,
23617–23624.
(10) (a) Beau, J.-M.; Gallagher, T. Top. Curr. Chem. 1997, 187, 1–54. (b)
Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913–9959. (c)
Liu, L.; McKee, M.; Postema, M. H. D. Curr. Org. Chem. 2001, 5, 1133–1167.
(11) Rutishauser, U. Nature ReV. Neurosci. 2008, 9, 26–35.
(12) (a) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J. J. Am. Chem. Soc.
1997, 119, 1480–1481. (b) Du, Y.; Polat, T.; Linhardt, R. J. Tetrahedron Lett.
1998, 39, 5007–5010. (c) Bazin, H. G.; Du, Y.; Polat, T.; Linhardt, R. J. J. Org.
Chem. 1999, 64, 7254–7259. (d) Kuberan, B.; Sikkander, S. A.; Tomiyama, H.;
Linhardt, R. J. Angew. Chem., Int. Ed. 2003, 42, 2073–2075. (e) Dino, K. R.;
Baytas, S. N.; Wang, Q.; Mun˜oz, E. M.; Tukuzoki, K.; Tomiyama, H.; Linhardt,
R. J. J. Org. Chem. 2005, 70, 8197–8200. (f) Yuan, X.; Ress, D. K.; Linhardt,
R. J. J. Org. Chem. 2007, 72, 3085–3088.
(13) (a) Abdallah, Z.; Doisneau, G.; Beau, J.-M. Angew. Chem., Int. Ed. 2003,
42, 5209–5212. (b) Malapelle, A.; Abdallah, Z.; Doisneau, G.; Beau, J.-M.
Angew. Chem., Int. Ed. 2006, 45, 6016–6020. (c) Malapelle, A.; Coslovi, A.;
Doisneau, G.; Beau, J.-M. Eur. J. Org. Chem. 2007, 314, 5–3157.
(14) Boons, G.-J. Tetrahedron 1996, 52, 1095.
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Perkins, B.; Wenger, J. D.; Stephens, D. S. Proc. Natl. Acad. Sci. U.S.A. 1997,
94, 271–276.
(3) Robbins, J. B.; McCracken, G. H.; Gotschlich, E. C.; Ørskov, F.; Ørskov,
I.; Hanson, L. A. N. Engl. J. Med. 1974, 290, 12216–12220.
(4) Theodosis, D. T.; Rougon, G.; Poulain, D. A. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 5494–5498.
(5) Hoffman, S.; Sorkin, B. C.; White, P. C.; Brackenbury, R.; Mailhammer,
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10.1021/jo801946y CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9497–9500 9497

SCHEME 1
SCHEME 2
oligosialic acids. The synthesis of C-glycosylation aldehyde
acceptor 6 and sulfone donor 8 was straightforward from the
known C-9 PMB protected compound 112f (Scheme 1). Prop-
argylation of hydroxyl groups of 1 with propargyl bromide in
the presence of barium hydroxide and barium oxide in DMF
afforded the propargylated carboxylic acid derivative 2 in a
modest 50% yield. Methylation of the carboxylic acid using
TMSCHN2 gave methyl ester 3 in 95% yield. Acetylation of
the acetamido group in 3, required to prevent intramolecular
cyclization reaction at later stage in the synthesis, was performed
by reaction with isopropenyl acetate in the presence of a catalytic
amount of p-toluenesulfonic acid to afford 4 in 96% yield. The
PMB protecting group on C-9 of compound 4 was chemose-
lectively removed using trifluoroacetic acid in DCM at -20
°C, affording 5 in 75% yield. Oxidation of the resulting C-9
hydroxyl group using the mild Dess-Martin periodinane
oxidizing agent afforded the desired aldehyde acceptor 6 in 95%
yield. The aldehyde group of 6 was protected with salicylic
diol,15 a photolabile carbonyl protecting group, to afford the
fully protected acetal derivative 7 as a single diastereomer in
83% yield. The aldehyde derivative 6 could be recovered by
photochemical deprotection of 7 in 60% yield using a 450 W
medium-pressure mercury lamp fitted with a Pyrex filter sleeve
to minimize undesired side reactions, demonstrating the utility
of this photolabile aldehyde protecting group. The target sulfone
donor 8 was obtained in 85% yield through the oxidation of
compound 7 with 3-chloroperbenzoic acid.
confirmed by the presence of NOEs, in the 2D-ROESY
spectrum, between H-4, H-6 and the methyl ester protons; such
NOEs would only be observed in an R-sialoside adopting the
5C2 conformation. The absolute configuration of the newly
formed hydroxymethylene group was also identified in the same
2D-ROESY spectrum, which showed close spatial proximity
between H-3ax and H-9′. The Felkin-Ahn model17 can be used
to predict the stereochemical outcome of a kinetically controlled
addition of a nucleophile to a prochiral aldehyde. The bulkiest
ligand R to the carbonyl group in 9R, the oxygen atom bearing
propargyl group at C-8′, has a perpendicular relationship to the
plane of the carbonyl group. The incoming nucleophile ap-
proaches to the carbonyl group through the Bu¨rgi-Dunitz
trajectory18 anticlinal to the bulkiest oxygen atom at C-8′,
resulting in R-configuration. Based on this analysis, shown in
Scheme 2, and the presence of an NOE between H-3ax and
H-9′, the R-configuration was confirmed.
Having the proper sulfone donor 8 and aldehyde acceptor 6
in hand, C-glycosylation was performed under the standard
Barbier conditions.16 As shown in Scheme 2, only one diaste-
reoisomer 9R was obtained in 70% yield, based on the consumed
donor. Structural analysis of 9R was performed using 1D and
1
2D NMR experiments including H NMR, 13C NMR, COSY,
HSQC, TOCSY, and ROESY (see the Supporting Information).
Initially, all protons and carbons were assigned. Next, their
through-bond and through-spatial correlations were determined.
The R-configuration of the newly formed C-glycoside was
(15) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 1533–1535.
(16) Excellent reviews on the application of SmI2: Molander, G.; Harris, C.
Chem. ReV. 1996, 96, 307–338.
(17) Anh, N.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61–70.
(18) Bu¨rgi, H.; Dunitz, J.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065–
5067.
9498 J. Org. Chem. Vol. 73, No. 23, 2008

chromatography (25% ethyl acetate in hexane) to afford 5 (1.59 g,
75%): Rf ) 0.27 (ethyl acetate/hexane, 1/1); H NMR (500 MHz,
Experimental Section
1
Methyl [Phenyl 5-acetamido-9-O-(p-methoxybenzyl)-3,5-dideoxy-
4,7,8-tri-O-propargyl-2-thio-D-glycero-r-D-galacto-non-2-ulopyra-
nosid]onate (3). Propargyl bromide (18.7 mL, 168 mmol),
Ba(OH)2 ·8H2O (13.2 g, 42 mmol), and BaO (12.9 g, 84 mmol)
were added successively to a solution of compound 1 (4.5 g, 8.4
mmol) in anhydrous DMF (100 mL) at room temperature. After
being stirred overnight, the reaction mixture was quenched by
addition of TsOH ·H2O (15.9 g, 84 mmol) and then diluted with
ethyl acetate (300 mL). After washing with saturated aqueous
NH4Cl (300 mL), the organic phase was dried (MgSO4) and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (DCM/MeOH, 20/1) to afford
phenyl 5-acetamido-9-O-(p-methoxy)benzyl-3,5-dideoxy-4,7,8-tri-
O-propargyl-2-thio-D-glycero-R-D-galacto-non-2-ulopyranosidic acid
(2) (2.67 g, 50%): Rf ) 0.15 (DCM/MeOH, 6/1). TMSCHN2 (2 M
in diethyl ether, 7.5 mL, 15 mmol) was added to a solution of 2 in
methanol/diethyl ether (1/1, 100 mL) at room temperature. After
being stirred for 3 h at the same temperature, the reaction mixture
was concentrated in vacuo. The residue was purified by silica gel
column chromatography (33% ethyl acetate in hexane) to afford 3
(2.60 g, 95%): Rf ) 0.25 (ethyl acetate/hexane, 2/1); 1H NMR (500
MHz, CDCl3) δ 7.55-7.53 (m, 2H, aromatic), 7.37-7.28 (m, 5H,
aromatic), 6.89-6.87 (m, 2H, aromatic), 5.48 (d, 1H, J ) 8.5 Hz),
4.53 (s, 2H), 4.47 (dd, 1H, J ) 2.5, 15.5 Hz), 4.26-4.19 (m, 2H),
4.15 (dd, 1H, J ) 2.5, 15.5 Hz), 4.05 (dd, 1H, J ) 2.5, 15.5 Hz),
3.97-3.93 (m, 2H), 3.89-3.86 (m, 2H), 3.80 (s, 3H), 3.74-3.68
(m, 3H), 3.62 (s, 3H), 3.61-3.59 (m, 1H), 2.94 (dd, 1H, J ) 4.5,
12.5 Hz), 2.48 (t, 1H, J ) 2.5 Hz), 2.44 (t, 1H, J ) 2.5 Hz), 2.38
(t, 1H, J ) 2.5 Hz), 1.95 (s, 3H), 1.79 (dd, 1H, J ) 11.5, 12.5 Hz);
13C NMR (125 MHz, CDCl3) δ 170.8, 169.1, 159.4, 137.1, 137.0,
130.5, 129.7, 129.6, 129.4, 128.9, 128.8, 113.9, 87.1, 81.1, 81.0,
80.2, 77.8, 76.5, 75.1, 74.9, 74.7, 74.5, 74.4, 74.2, 73.9, 73.2, 60.5,
58.2, 56.6, 55.6, 52.9, 50.7, 37.5, 24.0; HR MALDI-TOF MS m/z
calcd for C35H39NO9S [M + Na]+ 672.2238, found 672.2240.
Methyl [Phenyl 5-(N-acetylacetamido)-9-O-(p-methoxybenzyl)-
3,5-dideoxy-4,7,8-tri-O-propargyl-2-thio-D-glycero-r-D-galacto-non-
2-ulopyranosid]onate (4). A catalytic amount of TsOH ·H2O (190
mg, 1.0 mmol) was added to a solution of 3 (2.55 g, 3.92 mmol)
in isopropenyl acetate (50 mL) at room temperature. The reaction
mixture was heated to 60 °C and stirred for 5 h at the same
temperature. After quenching by addition of NEt3 (140 µL, 1.0
mmol), the reaction mixture was concentrated in vacuo. The residue
was purified by silica gel column chromatography (25% ethyl
acetate in hexane) to afford 4 (2.60 g, 96%): Rf ) 0.65 (ethyl
acetate/hexane, 2/1); 1H NMR (500 MHz, CDCl3) δ 7.55-7.53 (m,
2H, aromatic), 7.35-7.24 (m, 5H, aromatic), 6.89-6.87 (m, 2H,
aromatic), 4.67 (dd, 1H, J ) 2.5, 15.5 Hz), 4.54 (d, 1H, J ) 11.5
Hz), 4.47 (dd, 1H, J ) 2.5, 15.5 Hz), 4.45 (d, 1H, J ) 11.5 Hz),
4.67 (dt, 1H, J ) 5.0, 10.5 Hz), 4.27-4.17 (m, 3H), 4.15 (dd, 1H,
J ) 2.5, 15.5 Hz), 4.10-4.06 (m, 2H), 4.03-4.00 (m, 1H), 3.92
(t, 1H, J ) 10.0 Hz), 3.80 (s, 3H), 3.75 (t, 1H, J ) 3.0 Hz), 3.69
(dd, 1H, J ) 7.0, 11.0 Hz), 3.53 (s, 3H), 3.12 (dd, 1H, J ) 5.0,
13.0 Hz), 2.45 (s, 3H), 2.44 (t, 1H, J ) 2.5 Hz), 2.39-2.37 (m,
2H), 2.38 (s, 3H), 1.78 (dd, 1H, J ) 10.5, 13.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 175.9, 175.4, 168.5, 159.3, 136.9, 136.8,
130.9, 129.6, 129.4, 129.3, 129.0, 113.9, 88.5, 80.6, 79.5, 79.4,
79.3, 76.3, 75.7, 75.5, 75.4, 75.0, 74.7, 74.5, 73.2, 72.4, 59.9, 58.7,
58.0, 57.3, 55.6, 52.8, 40.0, 28.5, 26.0; HR MALDI-TOF MS m/z
calcd for C37H41NO10S [M + Na]+ 714.2343, found 714.2352.
CDCl3) δ 7.56-7.54 (m, 2H, aromatic), 7.44-7.35 (m, 3H,
aromatic), 4.57 (dd, 1H, J ) 2.0, 9.5 Hz), 4.49 (dd, 1H, J ) 2.5,
15.5 Hz), 4.32 (dt, 1H, J ) 5.0, 10.5 Hz), 4.30 (dd, 1H, J ) 2.5,
15.5 Hz), 4.19-4.06 (m, 5H), 3.92 (t, 1H, J ) 10.0 Hz), 3.76-3.72
(m, 3H), 3.60 (s, 3H), 3.15 (dd, 1H, J ) 5.0, 13.0 Hz), 2.47 (t, 1H,
J ) 2.5 Hz), 2.45 (s, 3H), 2.42 (t, 1H, J ) 2.5 Hz), 2.40 (s, 3H),
2.39 (t, 1H, J ) 2.5 Hz), 1.81 (dd, 1H, J ) 10.5, 13.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 175.8, 175.5, 168.6, 137.2, 130.5, 129.2,
129.0, 88.4, 82.5, 80.2, 79.4, 79.3, 75.9, 75.8, 75.7, 75.1, 75.0, 74.9,
72.1, 62.1, 59.9, 58.4, 58.3, 57.3, 52.9, 39.9, 28.6, 26.0; HR
MALDI-TOF MS m/z calcd for C29H33NO9S [M + Na]+ 594.1768,
found 594.1765.
Methyl [Phenyl 5-(N-acetylacetamido)-3,5-dideoxy-4,7,8-tri-O-
propargyl-2-thio-D-glycero-r-D-galacto-non-2-(9-oxaulopyranosi-
d)]onate (6). Dess-Martin periodinane solution (0.3 M in DCM,
36 mL, 10.7 mmol) was added slowly to a solution of 5 (1.53 g,
2.67 mmol) in DCM (100 mL) at 0 °C. After being stirred for 1 h
at 0 °C, the reaction mixture was warmed to room temperature
and then stirred for another 2 h. After quenching by adding of
aqueous 0.1 M Na2S2O3 solution (100 mL), the reaction mixture
was separated. The organic phase was washed with saturated
aqueous NaHCO3 (100 mL), dried over anhydrous MgSO4, and
filtered, and the filtrate was concentrated in vacuo. The residue was
purified by silica gel column chromatography (20% ethyl acetate
in hexane) to afford 6 (1.44 g, 95%): Rf ) 0.50 (ethyl acetate/
hexane, 1/1); 1H NMR (500 MHz, CDCl3) δ 9.76 (s, 1H),
7.50-7.35 (m, 5H, aromatic), 4.75 (dd, 1H, J ) 2.5, 9.5 Hz), 4.48
(d, 1H, J ) 1.0 Hz), 4.37 (dt, 1H, J ) 5.0, 10.5 Hz), 4.33-4.29
(m, 3H), 3.94 (t, 1H, J ) 10.0 Hz), 3.90 (dd, 1H, J ) 1.5, 2.0 Hz),
3.66 (s, 3H), 3.16 (dd, 1H, J ) 5.0, 13.0 Hz), 2.42 (s, 3H), 2.41 (s,
3H), 2.42-2.40 (m, 2H), 2.39 (t, 1H, J ) 2.5 Hz), 1.84 (dd, 1H,
J ) 11.0, 13.0 Hz); 13C NMR (125 MHz, CDCl3) δ 200.2, 175.7,
175.5, 168.7, 137.1, 130.6, 129.2, 129.0, 88.6, 84.9, 79.4, 78.8,
78.5, 77.1, 76.2, 76.0, 75.8, 75.1, 74.9, 72.2, 59.8, 58.2, 57.5, 57.3,
53.1, 40.0, 28.7, 26.0; HR MALDI-TOF MS m/z calcd for
C29H31NO9S [M + Na]+ 592.1612, found 592.1615.
Methyl [Phenyl 5-(N-acetylacetamido)-3,5-dideoxy-4,7,8-tri-O-
propargyl-2-thio-D-glycero-r-D-galacto-non-2-(9-oxa-ulopyranosi-
d)]onate 1′,1′-Diphenyl-5-methoxysalicylic Alcohol Acetal (7). A
catalytic amount of TsOH ·H2O (57 mg, 0.3 mmol) was added to
a solution of 6 (570 mg, 1.0 mmol) and 1′,1′-diphenyl-5-methox-
ysalicylic alcohol (920 mg, 3.0 mmol) in anhydrous benzene (20
mL) at room temperature. After being stirred for 1 day at the same
temperature, the reaction mixture was concentrated in vacuo. The
residue was purified by silica gel column chromatography (15%
ethyl acetate in hexane) to afford 7 (712 mg, 83%): Rf ) 0.45 (ethyl
acetate/hexane, 2/3); 1H NMR (500 MHz, CDCl3) δ 7.41-7.22 (m,
13H, aromatic), 7.14-7.11 (m, 2H, aromatic), 6.97 (d, 1H, J )
9.0 Hz, aromatic), 6.77 (dd, 1H, J ) 3.0, 9.0 Hz, aromatic), 6.40
(d, 1H, J ) 3.0 Hz, aromatic), 5.51 (d, 1H, J ) 3.0 Hz), 4.78 (dd,
1H, J ) 2.5, 9.5 Hz), 4.49 (dd, 1H, J ) 2.5, 15.5 Hz), 4.37 (dt,
1H, J ) 5.0, 10.5 Hz), 4.33 (dd, 1H, J ) 2.5, 15.5 Hz), 4.23 (d,
2H, J ) 2.0 Hz), 4.15-4.07 (m, 3H), 3.99 (t, 1H, J ) 10.0 Hz),
3.87 (dd, 1H, J ) 2.5, 15.5 Hz), 3.62 (s, 3H), 3.31 (s, 3H), 3.10
(dd, 1H, J ) 5.0, 12.5 Hz), 2.48 (s, 3H), 2.42 (t, 1H, J ) 2.5 Hz),
2.40 (s, 3H), 2.38 (t, 1H, J ) 2.5 Hz), 2.21 (t, 1H, J ) 2.5 Hz),
1.73 (dd, 1H, J ) 11.0, 12.5 Hz); 13C NMR (125 MHz, CDCl3) δ
176.0, 175.2, 168.5, 153.3, 146.1, 146.0, 143.8, 136.8, 129.9, 129.6,
128.7, 128.4, 128.2, 128.1, 127.7, 126.0, 118.4, 114.9, 114.4, 95.3,
88.0, 84.6, 80.3, 79.8, 79.6, 77.7, 75.6, 75.0, 74.8, 74.6, 72.5, 59.6,
59.5, 57.3, 56.8, 55.8, 52.5, 39.8, 28.6, 25.9; HR MALDI-TOF MS
m/z calcd for C49H47NO11S [M + Na]+ 880.2762, found 880.2774.
Methyl [Phenyl 5-(N-acetylacetamido)-3,5-dideoxy-4,7,8-tri-O-
propargyl-2-thio-D-glycero-r-D-galacto-non-2-ulopyranosid]onate
(5). Trifluoroacetic acid (7.0 mL) was added to a solution of 4 (2.60
g, 3.75 mmol) in DCM (50 mL) at -20 °C. After being stirred for
1 h at the same temperature, the reaction mixture was quenched
with saturated aqueous NaHCO3 (100 mL). After separation, the
organic phase was dried (MgSO4) and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by silica gel column
Photochemical Reaction To Remove the Photolabile Aldehyde
Protecting Group. A solution of acetal 7 (20 mg, 0.023 mmol) in
acetonitrile (20 mL) was photolyzed at room temperature for 80
min. After photolysis, the reaction mixture was concentrated in
J. Org. Chem. Vol. 73, No. 23, 2008 9499

vacuo and then purified by silica gel column chromatography (20%
ethyl acetate in hexane) to afford aldehyde 6 (8.6 mg, 60%).
Methyl 5-(N-Acetylacetamido)-3,5-dideoxy-4,7,8-tri-O-propar-
gyl-2-phenylsulfonyl-D-glycero-r-D-galacto-non-2-(9-oxaulopyra-
nosid)]onate 1′,1′-Diphenyl-5-methoxysalicylic Alcohol Acetal (8).
3-Chloroperbenzoic acid (233 mg, 60%, 0.94 mmol) was added to
a solution of 7 (270 mg, 0.31 mmol) in DCM (15 mL) at 0 °C.
After being stirred for 1 h at the same temperature, the reaction
mixture was warmed to room temperature and then stirred for
another 1 h to complete the reaction. Then, the reaction mixture
was quenched by aqueous 0.1 M Na2S2O3 solution (30 mL),
separated, and washed with saturated aqueous NaHCO3 (30 mL).
The organic phase was dried over anhydrous MgSO4 and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (15% ethyl acetate in hexane)
to afford 8 (233 mg, 85%): Rf ) 0.35 (ethyl acetate/hexane, 2/3);
1H NMR (500 MHz, CDCl3) δ 7.84-7.82 (m, 2H, aromatic),
7.64-7.61 (m, 1H, aromatic), 7.50-7.47 (m, 2H, aromatic),
7.37-7.25 (m, 10H, aromatic), 6.92 (d, 1H, J ) 9.0 Hz, aromatic),
6.77 (dd, 1H, J ) 3.0, 9.0 Hz, aromatic), 6.40 (d, 1H, J ) 3.0 Hz,
aromatic), 5.32 (d, 1H, J ) 2.5 Hz, H9), 4.83 (dd, 1H, J ) 2.0,
10.0 Hz, H6), 4.53 (dt, 1H, J ) 4.5, 10.5 Hz, H4), 4.27 (dd, 1H,
J ) 2.5, 15.5 Hz, OCH2CCH), 4.21 (dd, 1H, J ) 2.5, 15.5 Hz,
OCH2CCH), 4.16 (dd, 1H, J ) 2.5, 15.5 Hz, OCH2CCH), 4.11
(dd, 1H, J ) 2.5, 15.5 Hz, OCH2CCH), 3.99 (t, 1H, J ) 10.0 Hz,
H5), 3.95 (dd, 1H, J ) 2.5, 15.5 Hz, OCH2CCH), 3.88 (dd, 1H, J
) 2.5, 15.5 Hz, OCH2CCH), 3.76 (s, 3H, COOCH3), 3.74 (dd, 1H,
J ) 2.0, 8.5 Hz, H7), 3.65 (dd, 1H, J ) 2.0, 8.5 Hz, H8), 3.63 (s,
3H, OCH3), 3.25 (dd, 1H, J ) 4.5, 12.5 Hz, H3eq), 2.47 (s, 3H,
CH3CO), 2.42 (t, 1H, J ) 2.5 Hz, OCH2CCH), 2.40 (t, 1H, J )
2.5 Hz, OCH2CCH), 2.36 (s, 3H, CH3CO), 2.09 (dd, 1H, J ) 11.0,
12.5 Hz, H3ax), 2.01 (t, 1H, J ) 2.5 Hz, OCH2CCH); 13C NMR
(125 MHz, CDCl3) δ 175.9, 175.0, 165.7, 153.5, 145.8, 145.7,
143.9, 134.8, 134.4, 131.2, 129.8, 129.0, 128.4, 128.3, 128.2, 127.8,
125.9, 118.4, 115.0, 114.4, 95.6, 94.7, 84.9, 80.2, 79.9, 79.2, 76.7,
75.6, 75.1, 75.0, 74.8, 73.8, 71.7, 59.6, 58.8, 57.1, 56.8, 55.8, 53.9,
32.6, 28.4, 25.; HR MALDI-TOF MS m/z calcd for C49H47NO13S
[M + Na]+ 912.2660, found 912.2676.
temperature. After quenching by aqueous 0.1 M Na2S2O3 solution
(2 mL), the reaction mixture was diluted with DCM (3 mL),
separated, and washed with saturated aqueous NaHCO3 (5 mL).
The organic phase was dried over anhydrous MgSO4 and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (20% ethyl acetate in hexane)
to afford 9R {8 mg, 70%, calculated based on consumed donor 8
(8 mg)}: Rf ) 0.45 (ethyl acetate/hexane, 1/1); 1H NMR (500 MHz,
CDCl3) δ 7.57-7.23 (m, 15H, aromatic), 6.92 (d, 1H, J ) 9.0 Hz,
aromatic), 6.77 (dd, 1H, J ) 3.0, 9.0 Hz, aromatic), 6.42 (d, 1H, J
) 3.0 Hz, aromatic), 5.53 (d, 1H, J ) 4.5 Hz, H9), 5.23 (dd, 1H,
J ) 2.0, 10.0 Hz, H6), 4.75 (dd, 1H, J ) 2.5, 10.0 Hz, H6′),
4.54-4.40 (m, 4H, 4 × OCH2CCH), 4.35-4.29 (m, 3H, 2 ×
OCH2CCH, H4′), 4.27-4.18 (m, 4H, OCH2CCH, H9′, H4, H8),
4.10-4.02 (m, 4H, 3 × OCH2CCH, H8′), 4.00 (dd, 1H, J ) 2.5,
15.5 Hz, OCH2CCH), 3.91 (d, 1H, J ) 2.5 Hz, H7′), 3.87 (t, 1H,
J ) 10.0 Hz, H5), 3.85 (s, 3H, COOCH3′), 3.82-3.75 (m, 3H,
OCH2CCH, H5′, H7), 3.64 (s, 3H, OCH3), 3.54 (s, 3H, COOCH3),
3.12 (dd, 1H, J ) 4.5, 13.5 Hz, H3eq), 3.04 (d, 1H, J ) 10.5 Hz,
OH), 2.77 (dd, 1H, J ) 5.0, 13.0 Hz, H3′eq), 2.50 (s, 3H, CH3CO),
2.46 (t, 1H, J ) 2.5 Hz, OCH2CCH), 2.45 (s, 3H, CH3CO), 2.41
(t, 1H, J ) 2.5 Hz, OCH2CCH), 2.40 (t, 1H, J ) 2.5 Hz,
OCH2CCH), 2.38 (s, 6H, 2 × CH3CO), 2.32 (t, 1H, J ) 2.5 Hz,
OCH2CCH), 2.30 (t, 1H, J ) 2.5 Hz, OCH2CCH), 2.28 (t, 1H, J
) 2.5 Hz, OCH2CCH), 1.76 (dd, 1H, J ) 11.5, 13.5 Hz, H3ax),
1.53 (dd, 1H, J ) 10.5, 13.0 Hz, H3′ax); 13C NMR (125 MHz,
CDCl3) δ 176.0, 175.9, 175.4, 174.8, 171.7, 169.5, 153.4, 146.1,
145.5, 143.7, 137.3, 130.4, 129.6, 129.3, 128.9, 128.5, 128.4, 128.2,
128.1, 127.7, 125.9, 118.4, 115.1, 114.5, 95.0, 87.8, 84.6, 84.3,
81.4, 80.4, 80.1, 79.7, 79.5, 79.4, 78.9, 78.1, 77.8, 76.2, 75.7, 75.3,
75.2, 75.1, 74.9, 74.7, 74.4 (2), 72.6 (2), 72.0, 60.5, 59.8, 59.6,
59.2, 58.7, 57.6, 57.3, 56.4, 55.8, 53.1, 52.4, 40.0, 37.3, 29.9, 28.6,
28.4, 25.9 (2); HR MALDI-TOF MS m/z calcd for C72H74N2O20S
[M + Na]+ 1341.4448, found 1341.4452.
Acknowledgment. We thank Dr. Scott McCallum and Dr.
Herb Schwartz for their help with 2D NMR and support from
the NIH in the form of Grant No. AI065787.
Methyl 5-(N-Acetylacetamido)-3,5-dideoxy-2-C-{(9′R)-[methyl
(phenyl 5′-(N-acetylacetamido)-3′,5′-dideoxy-4′,7′,8′-tri-O-propar-
gyl-2′-thio-D-glycero-r-D-galacto-non-2′-ulopyranosid)]onate}-4,7,8-
tri-O-propargyl-D-glycero-r-D-galacto-non-2-(9-oxaulopyranosi-
d)]onate 1′,1′-Diphenyl-5-methoxysalicylic Alcohol Acetal (9R).
SmI2 solution (0.63 mL, 0.1 M in THF, 0.063 mmol) was added to
a mixture of sulfone donor 8 (14 mg, 0.0157 mmol) and aldehyde
acceptor 6 (12 mg, 0.021 mmol) and stirred for 5 min at room
Supporting Information Available: General procedures and
1H and 13C NMR spectra for all compounds 3-9R and COSY,
HSQC, TOCSY, ROESY, and HR ESI-MS spectra for disac-
charide 9R. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801946Y
9500 J. Org. Chem. Vol. 73, No. 23, 2008