Synthesis of S-linked N-acetylneuraminic acid derivatives via photoinduced thiol-ene and thiol-yne couplings

Article abstract of DOI:10.1055/s-0032-1318480

Thio-linked mono- and bivalent mimetics of α(2→3) and α(2→6)-linked sialosides were prepared by photoinduced hydrothiolation of alkenes and alkynes with the 2-mercapto sialic acid. Thiosialylation of 6-O-allyl- or 3-O-allyl-substituted galactose derivativ

Full text of DOI:10.1055/s-0032-1318480

LETTER
▌719
lSetyternthesis of S-Linked N-Acetylneuraminic Acid Derivatives via Photoinduced
Thiol–ene and Thiol–yne Couplings
Synthesis of S-Linked N-Acetylneuraminic Acid Derivatives
Magdolna Csávás,*a,b Mihály Herczeg,b,c Anikó Borbás*a
a
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, PO Box 70, 4010 Debrecen, Hungary
Fax +36(52)512914; E-mail: csavas.magdolna@science.unideb.hu; E-mail: borbas.aniko@pharm.unideb.hu
b
Research Group for Carbohydrates of the Hungarian Academy of Sciences, P.O. Box 94, 4010 Debrecen, Hungary
c
Department of Organic Chemistry, University of Debrecen, PO Box 20, 4010 Debrecen, Hungary
Received: 23.01.2013; Accepted after revision: 26.02.2013
While anionic addition of 1-thiolates to sugar enones
Abstract: Thio-linked mono- and bivalent mimetics of α(2→3) and
(termed thiol Michael addition)4 or free-radical addition
α(2→6)-linked sialosides were prepared by photoinduced hydrothi-
of thiols to alkenes (termed thiol–ene coupling)5 have al-
ready been successfully applied to generate thioglycosidic
olation of alkenes and alkynes with the 2-mercapto sialic acid. Thio-
sialylation of 6-O-allyl- or 3-O-allyl-substituted galactose
derivatives has been carried out by the thiol–ene click reaction. linkages, the neuraminic acid thiol has not been incorpo-
Double thiosialylation has also been achieved via thiol–yne chem-
istry using propargylated galactose derivatives as the alkyne com-
ponents and the peracetylated 2-mercapto sialic acid as the thiol.
rated within these strategies until now. Recently, the rad-
ical-mediated hydrothiolation of terminal alkyne, which
serves to introduce two thiol fragments across a carbon–
Key words: carbohydrates, N-acetylneuraminic acid, radical addi-
tions, thiol–ene/thiol–yne coupling, thiosialosides
carbon triple bond, has been exploited as an approach to
the synthesis of dendrimers,6 highly cross-linked polymer
networks,7 or polyfunctional materials.8 However, the thi-
ol–yne reaction has not been widely used in the field of
N-Acetylneuraminic acid (Neu5Ac), the most abundant
sialic acid, is an important constituent of various cell-sur-
face glycolipids and O- and N-linked glycoproteins. It is
typically found at the nonreducing end of glycan chains
anchored to galactosides through the α(2→3) or α(2→6)
linkage, or to N-acetyl galactosamine through the α(2→6)
linkage. Being at the terminus of glycoconjugates,
Neu5Ac is ideally positioned to mediate a wide variety of
biological processes, such as cell–cell interactions, cell
differentiation, extravasation of leukocytes, tumor metas-
tasis, and bacterial or viral infections.1
carbohydrate chemistry, with only few articles published
recently,9 none of which report the synthesis of thiosialo-
side derivatives. Thus, the potential of free-radical hydro-
thiolation as a powerful, metal-free ligation process for
the synthesis of S-linked N-acetylneuraminic acid deriva-
tives remains to be established.
Herein, we report on the synthesis of thiosialosides by
photoinduced hydrothiolation of allyl- and propargyl-
functionalized galactose derivatives with the peracetylat-
ed 2-mercapto sialic acid 1.
The reaction of the easily available 6-O-allyl substituted
galactose derivative 210 with thiol 111 was investigated ini-
tially, in the presence of the cleavable photoinitiator 2,2-
dimethoxy-2-phenyl-acetophenone (DPAP)12 at room
temperature by irradiation with UV lamp (λ = 365 nm).13
Using a thiol/ene ratio of 2:1 the reaction went to comple-
tion after 30 minutes affording the thio-linked pseudo-
disaccharide 314 in 85% isolated yield (Scheme 1).
Thiosialosides are hydrolytically stable analogues of the
native O-glycosides of Neu5Ac that have attracted partic-
ular interest from synthetic and medicinal chemists, as bi-
ological probes and potential inhibitors of sialic acid
recognizing proteins.2 Sialic acid thioglycosides are gen-
erally synthesized by S-alkylation of a 2-mercapto sialic
acid derivative or glycosylation of a thiol with a conven-
tional sialyl donor.3
AcO
OAc
COOMe
S
AcO
AcO
O
O
O
O
O
COOMe
SH
OAc
AcHN
AcO
O
i
O
O
O
O
AcO
+
AcHN
O
AcO
O
O
O
1
2
3
Scheme 1 Reagents and conditions: 1 (2 equiv), DPAP (2 × 0.1 equiv), toluene, r.t., hν (365 nm), 2 × 15 min (85%).
SYNLETT 2013, 24, 0719–0722
Advanced online publication: 08.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318480; Art ID: ST-2013-D0075-L
© Georg Thieme Verlag Stuttgart · New York

720
M. Csávás et al.
LETTER
AcO
COOMe
S
OAc
AcO
AcO
+
AcO
O
O
COOMe
S
O
OAc
AcO
i
AcO
O
O
AcHN
O
O
O
1 +
O
O
O
AcHN
MeOOC
OAc
O
AcO
O
S
O
O
O
O
AcO
O
AcHN
O
O
O
AcO
4
5
6
Scheme 2 Reagents and conditions: 1 (4 equiv), DPAP (2 × 0.1 equiv), hν (365 nm), toluene, r.t., 90 min (82% for 5, 11% for 6).
Then, photoinduced reaction13 between thiol 1 and the 6- thermodynamically more stable, E-isomer of the interme-
O-propargylated galactose derivative 415 was examined. It diate vinyl sulfide 5. 13C NMR analysis revealed that com-
is important to note that the radical thiol–yne reaction is a pound 6 had been obtained as a ca. 1:1 mixture of
two-step process. The first step involves the addition of a diastereomers as evidenced by four signals for C-2 of the
thiol to the C≡C bond to yield an intermediate vinyl sul- sialyl residues at δ = 82.8–83.5 ppm.17 Unfortunately, our
fide that subsequently undergoes a second, formally thiol– efforts to separate the isomers were unsuccessful due to
ene, reaction with additional thiol yielding the dithioether their very similar chromatographic behavior.
with exclusive 1,2-addition mode.9a In our case, with a thi-
ol/yne ratio of 4:1, the formation of two products was ob-
served after 30 minutes, the ratio of which remained
Next, compound 11 bearing a 3-O-allyl group and at-
tached to an acetal-protected octylaldehyde aglycon was
prepared to access a mimetic of the α(2→3)-linked sialo-
unchanged even in prolonged exposure to UV light. The
sides (Scheme 3). We envisaged that introduction of the
main product turned out to be an inseparable 7:3 mixture
aldehyde spacer at the anomeric position would make the
pseudodisaccharide able to be conjugated for biological
testing via reductive amination, a methodology that is
compatible with the carboxylic acid group of the N-acetyl-
of the E- and Z-isomers of the vinyl sulfide 5. The ratio of
the isomers was determined by 1H NMR spectroscopy of
the mixture based on the coupling constants of the vinyl
hydrogens.16 Despite the high excess of the thiol reagent,
neuraminic acid. The appropriately protected hydroxyal-
the doubly sialylated pseudotrisaccharide 6 was formed as
dehyde 8 was obtained from octane-1,8-diol (7) by a
the minor product of the thiol–yne coupling reaction
literature procedure.18 The synthesis of galactoside 11 was
(Scheme 2). Reduced rates and conversions for 1,2-substi-
tuted internal enes have been observed previously, which
accomplished from diol 919 in three steps. Dibutylstanny-
lene-mediated regioselective alkylation20 and subsequent
was due to steric considerations and a reversible addition
benzoylation afforded thiogalactoside 10, reaction of
which with the masked hydroxyaldehyde 8 upon
NIS–TfOH activation provided 11. Photoinduced free-
of the thyil radical to the internal ene.12 The low efficiency
of the second addition step between thiol 1 and the disub-
stituted alkene 5 could also be explained by the reversibil-
radical addition of thiol 1 to the 3-O-allylated galactoside
ity of the reaction and steric hindrance of the major,
O
ref. 16
HO
HO
O
OH
7
8
Ph
O
Ph
O
Ph
O
O
O
O
iii
i, ii
O
O
O
O
O
O(CH2)7
SPh
SPh
O
HO
O
OH
OBz
OBz
9
10
11
Ph
O
iv
O
OAc
OAc
COOMe
O
O
AcO
O
OBz
O(CH2)7
O
S
O
AcHN
AcO
12
Scheme 3 Reagents and conditions: i) 1. Bu2SnO, toluene, reflux, 3 h; 2. allyl bromide, CsF, DMF, 12 h (76%); ii) BzCl, pyridine, 3 h, 0 °C
(82%); iii) NIS–TfOH, CH2Cl2, 4 Å MS, 0 °C, 30 min (54%); iv) 1 (2 equiv), DPAP (2 × 0.1 equiv), toluene, r.t., hν (365 nm), 2 × 15 min
(85%).
Synlett 2013, 24, 719–722
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of S-Linked N-Acetylneuraminic Acid Derivatives
721
OAc
OAc
O
SPh
O
OAc
OAc
OAc
OAc
13
COOMe
S
OAc
AcO
O
O
O
i
O(CH2)7
O
O
AcHN
AcO
OAc
OAc
OAc
O
15
O
O
ii
+
O(CH2)7
O
OAc
OAc
OAc
COOMe
S
AcO
14
O
AcHN
OAc
OAc
O
O
O
AcO
O(CH2)7
OAc
OAc
O
COOMe
S
AcO
OAc
O
AcHN
AcO
16
Scheme 4 Reagents and conditions: i) 8 (1.5 equiv), NIS–TfOH, CH2Cl2, 4 Å MS, 0 °C, 30 min (46%); ii) 1 (4 equiv), DPAP (2 × 0.1 equiv),
hν (365 nm), toluene, r.t., 2 × 15 min (82% for 15, 12% for 16).
11 proceeded efficiently to produce the thiosialomimetic alic acid, incomplete reaction in the second addition step
1221 in 85% isolated yield.
and lack of diastereoselectivity were observed. Neverthe-
less, the thiol–yne approach provides an easy access to
novel vinyl sulfide type or dually glycosylated sialyl mi-
metics of biological interest. Further studies of these types
of compounds are in progress in our laboratory.
Finally, the 3-O-propargylated galactoside 14 was pre-
pared via NIS-TfOH promoted glycosylation of 8 with
thioglycoside 1322 and subjected to photoinduced cou-
pling with thiol 1 using a thiol/yne ratio of 4:1. The out-
come of the reaction was similar to that observed for
hydrothiolation of 4, showing the vinyl sulfide derivative
15 as the major product. The 1H NMR analysis of 15 re-
vealed, again, the presence of two diastereomers with the
prevalence of the E-isomer.23 Compound 16 as a doubly
sialylated mimetic of the α(2→3)-linked sialoside was ob-
tained in 12% yield (Scheme 4).
Acknowledgment
The work was supported by the TÁMOP 4.2.1/B-09/1/KONV-
2010-0007 project. The project is cofinanced by the European Uni-
on and the European Social Fund.
Supporting Information for this article is available online at
Deprotection of the sialylmimetics was demonstrated on
pseudodisaccharide 3. Zemplén deacetylation followed
by removal of the isopropylidene groups with HCl in
methanol and subsequent hydrolysis of the carboxylic es-
ter provided compound 17 in 27% overall yield (Scheme
5).
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
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References and Notes
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HO
OH
COOH
S
HO
O
O
AcHN
HO
HO
i, ii
O
3
HO
OH
OH
17
Scheme 5 Reagents and conditions: i) NaOMe, MeOH, overnight
(82%); ii) 1 M HCl, MeOH, 2 d, 50 °C (52%); iii) 0.2 M NaOH, 1,4-
dioxane (64%).
In conclusion, thiol–ene and thiol–yne couplings have
been used for the first time to achieve thio-linked mono-
and bivalent mimetics of the α(2→3)- and α(2→6)-linked
sialosides. The thiol–ene reactions took place by click-
type chemistry affording the pseudodisaccharides under
mild conditions and with excellent yields. During hydro-
thiolation of the propargyl moiety with the 2-mercapto si-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 719–722

722
M. Csávás et al.
LETTER
Vijayakrishnan, B.; Koeppe, J. R.; Davis, B. G. Angew.
Chem. Int. Ed. 2009, 48, 7798. (f) Fiore, M.; Marra, A.;
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(16) NMR Data for Compound 5
1H NMR (500 MHz, CDCl3): δ = 6.43* (d, 0.7 H, J = 15.5
Hz, SCH=CHCH2), 6.41* (d, 0.3 H, J = 8.5 Hz,
SCH=CHCH2), 5.93–5.88 (m, 1 H, SCH=CHCH2), 5.59–
5.52 (m, 2 H), 5.39–5.31 (m, 3 H), 4.89–4.85 (m, 1 H), 4.60–
4.57 (m, 1 H), 4.32–4.24 (m, 3 H), 4.16–4.03 (m, 4 H), 3.96–
3.88 (m, 2 H), 3.85–3.78 (m, 4 H), 3.63–3.53 (m, 2 H), 2.76–
2.71 (m, 1 H), 2.20–1.87 (m, 15 H), 1.54, 1.53, 1.44, 1.43,
1.34, 1.33, 1.32 (7 × s, 12 H, CH3,ip) ppm. 13C NMR (125
MHz, CDCl3): δ = 170.7, 170.5, 170.2, 169.9, 168.0, 167.9
(CO), 132.3, 128.5, 121.2, 120.3 (SCH=CHCH2), 109.0,
108.4 [(CH3)2C], 96. 2 (C-1), 84.2, 83.3 (2 × C-2′), 75.0,
74.3, 74.2, 71.0, 70.5, 70.4, 70.2, 69.5, 69.4, 68.9, 68.5, 67.6,
67.3, 67.2, 66.7, 66.6 (skeleton carbons), 71.1, 68.8, 68.5,
67.7, 62.1, 62.0 (C-6, C-9′, CH2), 53.0, 52.9 (2 × COOCH3),
49.0 (2 × C-5′), 37.5, 37.3 (2 × C-3′), 25.9, 25.8, 24.8, 24.3,
22.9, 21.0, 20.6 (CH3,Ac, CH3,NAc, CH3) ppm; *overlapping
signals.
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stereoselectivity during photoinduced addition of glucosyl
or galactosyl thiols to alkynyl peptides; see ref. 8a.
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Polym. Chem. 2004, 42, 5301.
(13) General Method for the Photoinduced Addition of 2-
Mercapto Sialic Acid 1 to Alkenes 2 and 8 and Alkynes 4
and 11
(21) NMR Data for Compound 12
1H NMR (360 MHz, CDCl3): δ = 8.06–7.26 (m, 10 H,
arom.), 5.60–5.43 (m, 3 H), 5.30–5.27 (m, 2 H), 5.14–5.12
(m, 1 H), 4.85–4.75 (m, 2 H), 4.57 (d, 1 H, J = 7.9 Hz), 4.50
(t, 1 H, J = 10.0 Hz), 4.45–4.35 (m, 3 H), 4.29–4.24 (m, 1 H),
4.15–3.87 (m, 8 H), 3.80–3.49 (m, 16 H), 2.60–2.54 (m, 2
H), 2.14–1.25 (m, 23 H) ppm. 13C NMR (90 MHz, CDCl3):
δ = 170.9, 170.6, 170.1, 170.0 (6 C, CO), 133.5-126.4 (10 C,
arom), 102.3, (2 C, Cac), 101.1 (C-1), 83.3 (C-2′), 78.5, 73.9,
73.2, 69.6, 68.3, 67.1, 66.7, 66.4 (8 C, skeleton carbons),
70.5, 69.3, 69.1, 68.0, 66.8 (5 C, 4 × CH2, C-6), 63.0 (C-9′),
52.8 (C-5′), 35.1, 32.7, 29.3, 29.2, 29.1, 25.8, 25.7, 25.5,
23.8, 23.7 (10 C, CH2), 23.1 (CH3,NHAc), 21.2, 20.8 (4 C,
CH3,Ac) ppm.
To a solution of the starting alkene or alkyne (1.00 mmol) in
dry toluene (5 mL), thiol (2.0–4.0 equiv) and 2,2-dimethoxy-
2-phenylacetophenone (DPAP, 2 × 25 mg, 2 × 0.10 mmol)
were added. The solution was deoxygenated and irradiated
with a UV lamp (λ = 365nm) at r.t. for 2 × 15 min. Then the
solution was concentrated, and the residue was purified by
column chromatography.
(14) NMR Data for Compound 3
1H NMR (500 MHz, CDCl3): δ = 5.52 (d, 1 H, H-1, J1,2 = 5.0
Hz), 5.34–5.31 (m, 3 H), 5.29 (d, 1 H, J = 10.5 Hz, NH),
4.89–4.83 (m, 1 H, H-4′), 4.59 (dd, 1 H, J1 = 8.0 Hz, J2 = 2.5
Hz, H-5′), 4.32–4.29 (m, 2 H), 4.25 (dd, 1 H, J1 = 8.0 Hz,
J2 = 2.0 Hz), 4.11 (dd, 1 H, J1 = 12.5 Hz, J2 = 4.5 Hz), 4.07–
4.01 (m, 1 H), 3.95–3.93 (m, 1 H), 3.83–3.80 (m, 1 H), 3.79
(s, 3 H, COOCH3), 3.64–3.48 (m, 3 H), 2.77–2.64 (m, 4 H),
2.15, 2.13, 2.04, 2.03 (4 × s, 12 H, 4 × CH3,Ac), 1.87 (s, 3 H,
CH3,NHAc), 1.85–1.77 (m, 2 H), 1.54, 1.44, 1.34, 1.33 (4 × s,
12 H, 4 × CH3) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.9–168.5 (6 × CO), 109.1, 108.4 [2 × (CH3)2C], 96.3
(C-1), 83.2 (C-2′), 74.1, 71.1, 70.6, 69.6, 68.7, 67.3, 66.6 (C-
2, C-3, C-4, C-5, C-4′, C-6′, C-7′, C-8′), 69.7, 69.4 (C-6,
OCH2) 62.1 (C-9′), 52.9 (OCH3), 49.3 (C-5′), 38.0 (C-3′),
29.4, 25.9 (OCH2CH2CH2S), 26.0, 25.7, 24.9, 24.4, 23.1
(4 × CH3,Ac, CH3,NHAc), 21.1, 20.8, 20.7 (4 × CH3) ppm.
(15) Yousuf, S. K.; Taneja, S. C.; Mukherjee, D. J. Org. Chem.
2010, 75, 3097.
(22) Giguère, D.; Patnam, R.; Bellefleur, M.-A.; St-Pierre, C.;
Sato, S.; Roy, R. Chem. Commun. 2006, 2379.
(23) NMR Data for Compound 15
1H NMR (500 MHz, CDCl3): δ = 6.46 (d, 0.17 H, J = 9.5 Hz,
SCH=CHCH2), 6.35 (d, 0.83 H, J = 15.5 Hz, SCH=CHCH2),
5.72–5.69 (m, 1 H, SCH=CHCH2), 5.48–5.31 (m, 3 H),
5.04–5.01 (m, 1 H), 4.90–4.85 (m, 2 H), 4.51–4.49 (m, 2 H),
4.40–4.17 (m, 3 H), 4.15–4.05 (m, 3 H), 4.01–3.75 (m, 10
H), 3.60–3.42 (m, 3 H), 2.75–2.72 (m, 2 H), 2.22–1.84 (m,
24 H), 1.59–1.28 (m, 14 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.7, 170.5, 170.4, 170.3, 170.2, 170.1, 170.0,
169.8, 169.4, 169.3, 168.1, 167.7 (CO), 130.5, 128.4, 122.2,
121.9 (CH), 102.3 (Cac), 101.2 (C-1), 77.2, 77.0, 76.7, 76.6,
76.1, 74.9, 74.4, 74.1, 70.7, 70.4, 69.8, 69.2, 68.8, 68.0, 67.3,
67.0, 66.7, 66.5, 65.9 (skeleton carbons), 69.5, 69.4, 67.5
(CH2), 62.2, 62.1, 61.9 (C-6), 53.0 (OCH3), 49.2, 49.0 (C-5),
37.5, 37.3, 35.1, 29.3, 29.1, 25.74 (CH2), 25.6, 23.7, 23.0,
21.1, 21.0, 20.9, 20.7, 20.6 (CH3) ppm.
Synlett 2013, 24, 719–722
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