Synthesis of a Carbon-Linked Mimic of the Disaccharide Component of the Tumor-Related SialylTn Antigen

Article abstract of DOI:10.1002/anie.200351969

The right mix! When one considers the many ways in which a polyfunctional organometallic species may be quenched before any productive C-C bond formation can occur (two amide protons, five esters), the samarium-promoted coupling between sulfide 1 and alde

Full text of DOI:10.1002/anie.200351969

Angewandte
Chemie
Stereoselective C-Sialylation
Synthesis of a Carbon-Linked Mimic of the
Disaccharide Component of the Tumor-Related
SialylTn Antigen**
Zouleika Abdallah, Gilles Doisneau, and Jean-
Marie Beau*
Among the large number of known tumor-associated carbo-
hydrate motifs, Tn (GalNAca1!O-Ser/Thr) and sialylTn
(Neu5Aca2!6GalNAca1!O-Ser/Thr) are the most specific
to human epithelial tumor cells (breast, colon, ovarian, lung,
and pancreatic cancers).[1] The sialylTn antigen, which is
expressed on membrane-bound mucin-type glycoproteins,
appears in transformed cells by premature sialylation of N-
acetylgalactosamine, the first sugar moiety of the nascent O-
glycane side chains in glycoproteins.[2] Integration of these
antigens into synthetic vaccine constructs induces an anti-
cancer immune response in which the carbohydrate domain
plays a decisive role in determining immunogenicity.[1,3] The
glycosylated antigen is, however, partially deglycosylated
during the priming period.[4] It is therefore important to
evaluate compounds in which the carbohydrate moiety
cannot be detached from the peptide. We previously reported
a mimic of the Tn antigen that could be incorporated into
immunogenic glycopeptides.[5] We now describe the easy
access to a carbon-linked mimic 2 of the Neu5Aca2!
6GalNAca1!OR disaccharidic component of the sialylTn
antigen (Scheme 1).[6,7]
Scheme 1. SialylTn tumor antigen 1 and a stable analogue of the sialyl-
N-acetylgalactosaminyl donor 2 for “block” synthesis.
[*] Prof. Dr. J.-M. Beau, Z. Abdallah, Dr. G. Doisneau
UniversitØ Paris-Sud
Laboratoire de Synth›se de BiomolØcules associØ au CNRS
Institut de Chimie MolØculaire et des MatØriaux
91405 Orsay Cedex (France)
Fax: (+33)1-6985-3715
E-mail: jmbeau@icmo.u-psud.fr
[**] We are grateful to Dr. P. Smith, GlaxoSmithKline, for a generous
supply of the N-acetylneuraminic acid used in this study.
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DOI: 10.1002/anie.200351969
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5209

Communications
ꢀ
The synthesis was designed in such a way that an activated
expected equatorial orientation of the newly formed C C
disaccharidic block would be available for modular attach-
ment to a wide variety of acceptors.[8] Integrated in a vaccine,
this segment would not be sensitive to enzymatic cleavage of
the sialyl and the galactosaminyl moieties. This stable mimic
may also be useful for the immunodiagnosis of different
tumors or for the affinity purification of specific receptors.
We previously established that a samarium diiodide
(SmI2) promoted Barbier reaction with glycosyl 2-pyridyl
sulfones is a rapid approach for the stereoselective assembly
of C-glycosides.[9–11] In an interesting extension to this work,
Linhardt and co-workers showed that the procedure worked
equally well with anomeric pyridyl sulfones of 2-ulosonic
esters.[12] They later reported that anomeric chlorides or
phenyl sulfones could also be used in this procedure without
the need of activation by hexamethyl phosphoramide
(HMPA).[13] These results were expected since reduction of
a functional group a to both an ester group and an oxygen
atom (Reformatsky-type reaction) is much more facile than
the same operation on a functional group a to an oxygen atom
alone. This observation suggests that functional groups other
than halides, sulfones, or phosphates would also be appro-
priate anomeric anion precursors for Neu5Ac or related
ulosonic acid derivatives. We report here a synthesis which
relies on the unprecedented use of a stable and crystalline 2-
pyridyl sulfide of the N-acetylneuraminic acid derivative 3 as
the anionic precursor in a samarium–Reformatsky proce-
dure.[14]
bond at the quaternary center was determined by NOE
measurements on both isomers of 4 (NOE contacts between
H1’ and H3eq/H3ax and not H4/H6). This stereochemical assign-
ment was further confirmed by the large values of the C1-H3ax
heteronuclear coupling constants observed in the deprotected
C-glycosyl compounds 5 (3J = 8.0 Hz for one isomer and
7.3 Hz for the other); these values are typical of a trans diaxial
orientation of the C1 C2 and C3 H3ax bonds.[18]
ꢀ
ꢀ
Preparation of the required aldehyde 12 (Scheme 3)
started from methyl a-d-N-acetylgalactosamine (6), which
was obtained by Fischer glycosylation[19] (MeOH, Dowex
The feasibility of this approach was first assessed with a
simple aldehyde and 2-pyridyl sulfide 3, which is available
from the corresponding 2-O-acetate (AcCl, AcOH, HCl[15a]
then 2-sulfanylpyridine (1.2 equiv), K2CO3 (1.3 equiv), tolu-
ene/acetone;[15b] 60% yield over the two steps). Treatment of
Scheme 3. Preparation of aldehyde 12. Reagents and conditions:
a) PhCH(OMe)2, CSA, DMF, 408C, 2 h, 60%; b) BnBr (3.5 equiv),
Ba(OH)2·8H2O, BaO, DMF, 258C, 77%; c) AcOH/H2O (70/30), 708C,
1 h, 88%; d) SOCl2, Et3N, CH2Cl2, 08C, 1 h; cat. RuCl3·3H2O, NaIO4,
CH3CN/CH2Cl2/H2O (2/2/3), 258C, 1 h, 65%; e) NaCN, DMF, 258C,
3 h, 97%; f) cat. H2SO4, moist THF, 258C, 1 h, 86%; g) TESOTf
(3 equiv), pyridine, DMAP, CH2Cl2, 08C, 0.5 h, 80%; h) DIBAL-H
(3.3 equiv in 3 portions every 20 min), CH2Cl2, ꢀ788C, 1 h, 60%.
CSA=camphorsulfuric acid, Bn=benzyl, TES=triethylsilyl, DMAP=4-
dimethylaminopyridine, DIBAL-H=diisobutylaluminum hydride.
a
solution of sulfide 3 and cyclohexanecarbaldehyde
(1.5equiv) in THF at 20 8C with a freshly prepared solution
of SmI2[16] in THF led to a very fast consumption of the one-
electron reducing agent.[17] After a standard workup, the C-
glycosyl derivatives 4 were obtained in an approximately 1:1
diastereomeric ratio and separated by chromatography (86%
yield; Scheme 2).
Both compounds displayed a standard C2-chair confor-
5
1
mation as determined by H NMR analysis (J3ax,4, J4,5, and
J5,6 values of 10.2, 11.8, and 10.5Hz, respectively, for one
isomer and of 12.0, 10.5, and 10.5 Hz for the other). The
50W-X8, H+ form, reflux, 24 h) of N-acetyl-d-galactosamine
or, more conveniently for large-scale preparations, by trans-
formation of the inexpensive N-acetyl-d-glucosamine.[20]
A standard three-step sequence provided diol 7 which
was converted into 4,6-cyclic sulfate 8 by using the
procedure of Gao and Sharpless.[22] Regioselective ring
opening of cyclic sulfate 8 at C-6[23] by sodium cyanide
provided cyanide sulfate 9 in high yield which, after
hydrolytic removal of the intermediate sulfate, gave
alcohol 10. This high-yielding one-carbon extension of
the sugar chain at position 6 is in stark contrast to all
attempts at nucleophilic displacement of iodides or
sulfonates by cyanide ions in the more conventional 6-
iodo (or 6-O-sulfonates) derivatives of N-acetyl-d-gal-
actosamine 13 with a variety of protecting groups at
positions 3 and 4 (OPG in 13, including OH groups).[24]
These attempts all failed and yielded only elimination
Scheme 2. SmI2-induced coupling of pyridyl sulfide 3 with cyclohexanecarbaldehyde.
2-Py=2-pyridyl. a) MeONa, MeOH, 208C, overnight; NaOH, MeOH-H2O, 208C, 2 h,
then Dowex 50W-X8-H+ form, 90%.
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Chemie
products.[25] Triethylsilylation at position 4 furnished 11, and
careful reduction of the nitrile with diisobutylaluminum
hydride at ꢀ788C provided the aldehyde 12, which was used
immediately after purification in the next step.[26] The
b-[32]selective C-glycosylations on a wide range of adapted
acceptors for different biological applications.
samarium–Reformatsky coupling procedure, as described Experimental Section
14: A 0.1m solution of SmI2 in THF (6.5mL, 0.65mmol of SmI 2) was
above, with sulfide 3 (1.5equiv) and aldehyde 12 afforded
the carbon-linked dimer 14 in high yield (93%) as a 1:1
diastereomeric mixture (Scheme 4).[27]
added to a stirred mixture of pyridyl sulfide 3 (151 mg, 0.26 mmol)
and freshly prepared aldehyde 12 (78 mg, 0.17 mmol) at 208C under
Ar. After stirring the mixture for 10 min, saturated aqueous NH4Cl
was added and the reaction mixture was extracted three times with
CH2Cl2. The combined organic phases were washed twice with water,
dried with Na2SO4, and evaporated to dryness. Flash chromatography
(toluene/acetone, 2/1) gave 14 (148 mg, 93%). Isomers of 14 were
separated at this stage (isomer ratio of 1:1). The following steps of the
synthesis are, however, carried on with the mixture. Selected data for
one of the isomers of 14: 1H NMR (CDCl3, 250 MHz, atom
numbering of the natural dimer): d = 7.36–7.25(m, 5H, Ph), 5.41
(ddd, J7’,8’ = 7.6, J8’,9’a = 6.9, J8’,9’b = 2.2 Hz, 1H, H-8’), 5.25 (dd, J7’,8’
7.6, J6’,7’ = 2.2 Hz, 1H, H-7’), 5.26 (d, JNH,5’ = 10.0 Hz, 1H, NH
Neu5Ac), 5.17 (d, JNH,2 = 9.6 Hz, 1H, NH Gal), 4.82 (ddd, J4’,3’ax
11.8, J4’,5’ = 10.1, J4’,3’eq = 4.4 Hz, 1H, H-4’), 4.71 and 4.39 (2 ” d, J =
=
=
12 Hz, 2H, CH2Ph), 4.61 (d, J1,2 = 3.7 Hz, 1H, H-1), 4.50 (ddd, J2,3
10.6, J2,NH = 9.6, J1,2 = 3.7 Hz, 1H, H-2), 4.34 (dd, J9’a,9’b = 12.2, J8’,9’b
2.2 Hz, 1H, H-9’b), 4.11 (d, J3,4 = 2.8 Hz, 1H, H-4), 4.01 (ddd, J5’,6’
10.2, J4’,5’ = 10.1, J5’,NH = 10 Hz, 1H, H-5’), 3.99 (dd, J9’a,9’b = 12.2, J8’,9’a
=
=
=
=
6.9 Hz, 1H, H-9’a), 3.92–3.82 (m, 2H, H-5,7), 3.89 (dd, J5’,6’ = 10.2,
J
J
6’,7’ = 2.3 Hz, 1H, H-6’), 3.76 (s, 3H, COOCH3), 3.42 (dd, J2,3 = 10.6,
3,4 = 2.8 Hz, 1H, H-3), 3.26 (s, 3H, OCH3), 2.71 (d, J7,OH = 11.2 Hz,
1H, OH), 2.47 (dd, J3’eq,3’ax = 12, J3’eq,4’ = 4.4 Hz, 1H, H-3’eq), 2.15,
2.09, 2.02, and 2.00 (4 ” s, 12H, OCOCH3), 1.84 (s, 3H, NCOCH3) 1.70
(dd, J3’eq,3’ax = 12, J3’ax,4 = 11.8 Hz, 1H, H-3’ax), 1.51–1.41 (m, 2H, H-
6a,b), 0.95(t, J = 7.9 Hz, 9H, CH3CH2Si), 0.65ppm (q, J = 7.9 Hz, 6H,
CH2Si); MS (ES): m/z = 949 [M+Na]+; HR-MS (ES) for C43H66Na-
N2O18Si; calcd: 949.3977; found: 949.3989.
Scheme 4. Preparation of the carbon-linked sialyl-N-acetylgalactosa-
minyl donor 17. Reagents and conditions: a) SmI2 (2.5 equiv), THF,
258C, 93%; b) (Imid)2CS (10 equiv), CH3CN, reflux, 4 h; c) Ph3SnH
(2.5 equiv), C6F5OH (1 equiv), cat. AIBN, toluene, reflux, 2 h, 65% over
two steps; d) MeOH/HClaq, 258C, 2 h, 95%; e) H2, Pd/C, EtOH, cat.
HClaq, 94%; f) Ac2O, pyridine, 94%; g) Ac2O/AcOH/H2SO4 (8/2/0.1),
258C, 6 h, 70%. Imid=imidazole, AIBN=azobisisobutyronitrile.
Selected data for 16; 1H NMR (CDCl3, 250 MHz, atom number-
ing of the natural dimer): d = 5.8 (d, JNH,5 = 9.5Hz, 1H, NH Gal),
5.55–5.28 (m, 3H, H-7’,8’,NH Neu5Ac), 5.19 (d, J3,4 = 2.9 Hz, 1H, H-
4), 5.08 (dd, J2,3 = 10.9, J3,4 = 2.9 Hz, 1H, H-3), 4.76 (ddd, J4’,3’ax = 12.5,
J
4’,5’ = 10.0, J4’,3’eq = 4.4 Hz, 1H, H-4’), 4.7 (d, J1,2 = 3.7 Hz, 1H, H-1),
4.51 (ddd, J2,3 = 10.9, J2,NH = 10.2, J1,2 = 3.7 Hz, 1H, H-2), 4.29 (dd,
9’a,9’b = 12.3, J9’a,8’ = 2.0 Hz, 1H, H-9’a), 4.05(dd, J9’a,9’b = 12.3, J8’,9’b
4.9 Hz, 1H, H-9’b), 3.97 (m, 1H, H-5’), 3.75(m, 2H, H-5,6 ’), 3.71 (s,
3H, COOCH3), 3.35(s, 3H, OCH ), 2.43 (dd, J3’eq,3’ax = 12.5, J3’eq,4’
J
=
Alcohols 14 were converted into thiocarbonates by treat-
ment with a large excess of N,N’-thiocarbonyldiimidazole in
refluxing acetonitrile and deoxygenated by employing triphe-
nyltin hydride, catalytic AIBN, and pentafluorophenol,[28]
which yielded the required C-disaccharide 15 as a single
compound (65% for the two steps). Desilylation, hydro-
genolysis, and acetylation provided the peracetylated C-dimer
16.[29] The high stability of the linkage between the N-
acetylneuraminyl and the N-acetylgalactosaminyl residues
now allows for modifications under conditions that are
unacceptable with a native O linkage. Thus, acetolysis of the
methyl glycoside in dimer 16 provided anomeric acetate 17,
which can be easily converted into other anomeric substitu-
ents usable in “block” synthesis.
In conclusion, the reductive samariation of a pyridyl
sulfide of methyl N-acetylneuraminate is a useful and high-
yielding approach for stereoselective a-C-sialylation. One
may notice here that anomeric sulfides of Neu5Ac are also
good glycosyl donors in stereoselective a-O-sialylation.[30] C-
Disaccharidic building block 17 can be readily transformed
into a variety of glycosyl donors for b-selective O-glycosyla-
tion by standard procedures, for a-selective O-glycosylation
by a modification of Koganti's procedure,[31] and a-[10] or
=
3
4.4 Hz, 1H, H-3’eq), 2.17, 2.09, 2.07, 2.00, 1.98, 1.95, and 1.93 (7 ” s,
21H, OCOCH3), 1.92 (m, 1H, H-6b), 1.84 (s, 3H, NCOCH3), 1.78–
1.70 (m, 2H, H-6a,7b), 1.72 (dd, J3’ax,3’eq = 12.5, J3’ax,4’ = 12.5Hz, 1H, H-
3’ax), 1.16 ppm (m, 1H, H-7a); MS (ES): m/z = 813 [M+Na]+; HR-
MS (ES) for C34H50NaN2O19; calcd: 813.2905; found: 813.2905.
Received: May 26, 2003 [Z51969]
Keywords: glycosides · metalation · reduction · samarium ·
.
sialic acids
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[25] This is in complete contrast to the good results obtained in other
series;[9f] see also N. Miquel, G. Doisneau, J.-M. Beau, Chem.
Commun. 2000, 2347.
[26] Concomittant reduction of the acetamido group also provided
20% of the corresponding N-ethyl derivative.
[6] Similar work appeared very recently: B. Kuberan, S. A.
Sikkander, H. Tomiyama, R. J. Linhardt, Angew. Chem. 2003,
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[27] It is interesting to note that the same samarium–Reformatsky
coupling reaction conducted with the corresponding anomeric
chloride failed,[13a] and provided only the reduction products of
both the chloride and the aldehyde 12 in high yield. Since this
aldehyde is unusually sensitive to reduction by SmI2, a much
faster transfer rate of the first electron in the pyridyl sulfide 3
(inner-sphere transfer) compared to that of the chloride (outer-
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[28] O. Jarreton, T. Skrydstrup, J.-M. Beau, Chem. Commun. 1996,
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3
[29] Besides NOE measurements and JC1,H3ax values as determined
in isomers 4, the stereochemical assignment of the quaternary
center in 16 (C-2’) may also be based on empirical data extracted
from simple 1D 1H NMR spectra: the chemical shift of H4’
(4.76 ppm in 16) and the Dd value of H9a-H9b (0.24 ppm in 16).
For the empirical rules with C-glycosides see refs. [12,13] and
with O-glycosides, see H. Paulsen, H. Tietz, Angew. Chem. 1982,
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Vauzeilles, J.-M. Beau in Oligosaccharides in Chemistry and
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Sinay¨, G. Hart), Wiley-VCH, Weinheim, 2000, p. 495; J.-M.
Beau, B. Vauzeilles, T. Skrydstrup in Glycoscience: Chemistry
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[14] For the reductive samariation of glycyl sulfide derivatives, see M.
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[16] a) P. Girard, J.-L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980,
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[17] The anomeric phenyl sulfide analogous to 2-pyridyl sulfide 3 is
unreactive under the conditions used. A complete study with
other anomeric substituents will be reported shortly.
[18] J. Haverkamp, T. Spoormaker, L. Dorland, J. F. G. Vliegenthart,
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[20] N-acetyl-d-glucosamine was transformed to methyl glycoside 6
by the following sequence:[21] a) MeOH, Dowex 50W-X8-H+
form
, 258C, 24 h; PivCl, pyridine, CH2Cl2, 08C; 80%
(2 steps); b) Tf2O, pyridine, DCE, H2O, 0 8C, 0.5h; H 2O, 90 8C,
5212
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Angew. Chem. Int. Ed. 2003, 42, 5209 –5212