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Bioconjugate Chemistry
1-O-Glycoconjugated H2S donors.
glycosylation method using the
A
general
glycoside.21 Indeed, O-acyl- or O-benzoyl- α-TCA provided
a β-stereoselective glycosylation in case of gluco- and
galacto-derivatives 4a, 4b, 6b, 15a, and 15b. On the other
1
2
3
4
5
6
7
8
O-glycosyl
trichloroacetimidates (TCA) 14 as the classical glycosyl
donor and the hydroxylated nucleophiles, such as
compounds 1, 2, and 3a, as the glycosyl acceptors was
employed for the synthesis of the series of 1-substituted
glycosyl derivatives 4, 6, and 15 (Scheme 2).16,17
hand,
a
α-stereoselectivity resulted from the
mannopyranosyl derivative 4c, which, contrarily to the
previously mentioned donors, contains the acyl
participating group linked at C2 position on the β-face of
the sugar. In the case of glycosyl-p-hydroxyaryl-
isothiocyanate 6a, in spite of the presence of the
participating acetyl group at C2 position, the glycosylation
process afforded a mixture of α- and β-glucopyranoside
derivatives (6aα/6aβ, 3:7 ratio), probably due to the
formation of the oxonium ion in the reaction process.22 The
glycosylation reaction for the glucopyranose aryl-
isothiocyanate 6a and the β-galactopyranosyl analogue 6b
were performed in 52% (3:7 ratio for the α/β anomers) and
36% yields, respectively. Also in this case, the presence of
the NCS group was confirmed by IR spectra displaying
intense and broad peaks between 2060-2130 cm-1, and by
13C NMR analysis, which showed the typical signal at
around 155 ppm (Figure 1 and Table S1 of Supporting
Information). Fully-O-acylated compound 4a was also
converted to its O-deprotected analogue 5a, by using a
freshly prepared solution of 0.33 M MeONa/MeOH.
Scheme 2. General glycosylation reaction with
TMSOTf (Condition a), or with Sc(OTf)3 (Condition b)
as catalyst (A); glycosylation of compound 1, 2 and 3a
(HO-Nu) and deacetylation step of compound 4a (B)a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A)
R
R2
R
R2
R4
R4
a or b
O
O
R3
R
R3
R
HO Nu
+
O
Nu
R1
NH
CCl3
R1
1 2 3a
, or
O
4a-c 6a-b
,
,
15a-b
1
3
2
4
14a
14b
14c
: R, R , R =OAc; R , R =H
1
4
2
3
: R, R , R =OAc or OBz; R , R =H
2
3
1
4
: R, R , R =OBz; R , R =H
S
S
B)
S
c
b
1
3
2
4
4a
5a:
R, R , R =OH; R , R =H
14a-c
+
1
4
2
3
4b
4c
: R, R , R =OBz; R , R =H
HO
2
3
1
4
: R, R , R =OBz; R , R =H
Since the isothiocyanate moiety would readily
decompose under Zemplén deprotection conditions, no
further deprotection treatments were carried out on
glycopyranosyl aryl-isothiocyanates 6a and 6b,23 which
were then tested as acylated glycoconjugated-H2S donors
(see Biopharmacology). Furthermore, it was not possible to
synthesize the isothiocyanate portion on the fully
1
NCS
1
3
2
4
a
6a
6b
: R, R , R =OAc; R , R =H
14a-b
14a-b
+
+
1
4
2
3
: R, R , R =OAc; R , R =H
HO
2
a
1
3
2
4
NHBoc
15a
15b
: R, R , R =OAc; R , R =H
HO
1
4
2
3
: R, R , R =OAc; R , R =H
3a
deprotected p-amino-aryl glycoside by following
a
a Reagents and Conditions: (a) TMSOTf, AW300, dry DCM (for
compounds 4c, 6a, 6b, and 15a, 15b); (b) Sc(OTf)3, AW300, dry
DCM (for compounds 4a and 4b); (c) 0.33 M MeONa, MeOH.
procedure similar to that described in Scheme 3 (which
was successfully utilized for the preparation of compounds
16a and 16b and their final transformations through steps
c and b of Scheme 3).13
Three α-trichloroacetimidate (α -TCA) derivatives 14a,
14b, and 14c, opportunely protected with acyl or benzoyl
functionalities at C2, C3, C4, and C6 positions, were
obtained starting from commercially available (+)-D-
Scheme 3. Synthesis of the final isothiocyanate
derivatives 7a, 7b, and 8a, 8ba
glucopyranose,
(+)-D-galactopyranose,
or
(+)-D-
mannopyranose.18, 19 Treatment of these intermediates with
glycosyl acceptors 1, 2, or 3a (HO-Nu, Scheme 2), in dry
CH2Cl2 and in the presence of AW300 molecular sieves (4
Å) and a suitable Lewis acid afforded anethole trithione
derivatives (4a, 4b and 4c), the fully-O-acyl-
glycopyranoside aryl isothiocyanates (6a-α, 6a-β, and 6b),
and the alkyl-N-Boc gluco- and galacto- pyranosides (15a
and 15b). Specifically, the glycosylation process efficiently
proceeded by using TMSOTf as the catalyst in the case of
glycosyl acceptors 2 and 3a (conditions a, Scheme 2).
Instead, in the case of compound 1, the glycosylation
proceeded with satisfactory yields only when using
Sc(OTf)3 as the catalyst (conditions b, Scheme 2).20 Overall,
the stereochemistry of the glycosylation process during the
glycosidic bond formation is generally influenced by the
neighbouring participating group at C2 position of the
glycosyl donor, which usually leads to the 1,2-trans-
3
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