Versatile intermediate for complete α/β stereocontrol in O-glycosidation reactions

Article abstract of DOI:10.1039/a705338j

β-O-Glucosides 5, which can be completely converted to the α-anomers in the reaction medium, are obtained as single isomers by glycosidation of readily available donor 1 and are easily transformed into 2-deoxy-β-O-glucosides.

Full text of DOI:10.1039/a705338j

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Versatile intermediate for complete a/b stereocontrol in O-glycosidation
reactions
Giuseppe Capozzi,*† Francesca Mannocci, Stefano Menichetti, Cristina Nativi* and Serena Paoletti
Centro CNR ‘Chimica e Struttura dei Composti Eterociclici’, Dipartimento di Chimica Organica, Universita’ di Firenze, via G.
Capponi, 9 I-50121 Firenze, Italy
b-O-Glucosides 5, which can be completely converted to the
a-anomers in the reaction medium, are obtained as single
isomers by glycosidation of readily available donor 1 and are
easily transformed into 2-deoxy-b-O-glucosides.
b-Glycosides 5 can be completely transformed into the
a-anomers 6 by letting the product isomerise under the same
reaction conditions; the isomerisation is presumably induced by
acid catalysis. The aforementioned turning colour visually
indicates the beginning of the isomerisation reaction, the time at
which this occurs depends on the individual glycoside (from 0.5
h for 6a to 1.5 h for 6d¶). Thus, a single glycosidation reaction
Stereocontrol in O-glycosidation is a central matter in carbohy-
drate chemistry. A wide number of biologically important
molecules originate from an aglycone and a saccharide by
formation of a glycosidic linkage, moreover entire classes of
polysaccharides are generated in nature by glycosidation of
simpler carbohydrates.1 A great effort has been devoted to
optimise the glycosidation reaction as an indispensable trans-
formation in organic chemistry. The crucial aspect has always
been the achievement of a good level of stereocontrol on the
formation of the glycosidic linkage, which usually leads to
mixtures of a and b anomers. Efforts in this area have met with
varying degrees of success.2 While methods affording the a
anomer with good selectivity are available, preparation of the
pure b anomer is still a rare achievement. The problem is more
serious for 2-deoxyglycosides, a class of derivatives of
biological relevance, where the lack of assistance from
proximal substituents and the low stability of precursors make
the preparation of pure anomers, particularly the b anomer, a
real challenge.3 Our approach to the stereoselective synthesis of
2-deoxyglycosides was based on the exploitation of inter-
mediates like 1. We report here a synthetic protocol for
O-glycosidation of tri-O-benzylglucal derivative 1 with com-
plete stereocontrol of the glycosidic linkage, affording in a
single reaction either a- or b-2-deoxyglucosides by simply
controlling the experimental conditions. To the best of our
knowledge, among the very few methods available, there is only
one report of a selective preparation of b-2-deoxyglucosides
that follows a similar approach.4 The substantial improvement
of the present protocol is the preparation of the b anomer as a
pure isomer by using the readily available acetate 1 and the
complete transformation of the b into the a anomer in the same
reaction medium. The procedure is outlined in Scheme 1.
The oxathiine 1 is obtained from 2 which in turn is prepared
in high yield as a single regioisomer by cycloaddition of tri-
O-benzylglucal 3 with 2,4-dioxopentane-3-thione in a 95 :5
a:b diastereomeric ratio.5,6 Subsequent reduction of the
carbonyl group to the alcohol and acetylation with acetic
anhydride under standard conditions gave quantitatively the
acetate 1, which is further reacted without purification after
removal under vacuum of pyridine and excess acetic anhydride.
The glycosidic donor 1 is reacted in dry nitromethane at room
temperature with the appropriate acceptor 4a–d in the presence
of a catalytic amount of methyl trifluoromethanesulfonate and
quenching the reaction with pyridine.‡ Timing of quench is
crucial for the success of b glycosidation. Quenching the
reaction at the turning of the colour of the mixture from pale
yellow to red affords the b glycosides 5 exclusively (reaction
times and yields are given in Table 1). The stereochemistry of
products is readily assigned by the chemical shift (d 4.3–4.4)
and coupling constants (J1,2 7.6–8.4 Hz) of the anomeric proton
BnO
BnO
BnO
BnO
O
O
BnO
BnO
BnO
i
ii, iii
O
S
S
BnO
BnO
O
O
O
AcO
3
2
1
iv
BnO
BnO
O
OR
BnO
BnO
vi
S
O
O
BnO
BnO
OR
7a, c, d
H
5a–d
v
HO
ROH :
HO
BnO
BnO
O
4a
4b
BnO
S
OR
H
HO
BnO
O
O
O
O
O
OMe
6
O
BnO
HO
O
BnO
4c
4d
Scheme 1 Reagents and conditions: i, see ref. 5; ii, LiAlH4 (0.5 equiv.),
THF, 0 °C to room temp., 30 min, 92%; iii, Ac2O, pyridine, room temp.,
96%; iv, ROH (2 equiv.), MeOTf (0.2 equiv.), MeNO2, room temp., v,
MeOTf (0.2 equiv.), MeNO2, room temp., 1 h, quantitative yield; vi, Raney-
Ni, wet THF, 0 °C to room temp.
Table 1 Reaction times and yields of 5 and 7
Entry
Compound
t/min
Yielda (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
7a
7c
7d
5
5
82
61
40
58
72
65
68
35
50
45
30
30
1
in the H NMR spectra.§ Chemically pure b-glycosides are
obtained by flash column chromatography.
a Isolated yield.
Chem. Commun., 1997
2291

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BnO
BnO
BnO
Footnotes and References
H+
–ROH
R
H
+
ROH
–H+
O
O
BnO
BnO
O
† E-mail: capozzi@chimorg.unifi.it
BnO
5
6
‡ Running the reaction in the presence of molecular sieves causes an
appreciable increase of reaction time (Table 1, entry 3: from 35 min to 2 h)
without a significant increase in yield (entry 3: from 40 to 43%).
§ Selected data for 5d: white solid, mp 98–100 °C; [a]D 27 (c 0.3, CHCl3);
dH(200 MHz, CDCl3, J/Hz) 2.05 (d, 3 H, J 6.6), 2.27 (s, 3 H), 2.37 (s, 3 H),
3.30–3.75 (m, 14 H), 3.94–3.99 (m, 1 H), 4.33 (d, 1 H, J 7.6), 4.47 (d, 1 H,
J 8.2), 4.45–4.97 (m, 12 H), 6.81 (q, 1 H, J 7.0), 7.10–7.41 (m, 30 H); dC(50
MHz, CDCl3) 16.7, 26.9, 52.1, 57.2, 68.2, 68.7, 73.5, 74.6, 74.7, 74.9, 75.6,
74.8, 75.1, 78.2, 78.6, 82.1, 83.3, 84.6, 104.3, 104.4, 127.5, 127.6, 127.8,
127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 138.0, 138.1, 138.3, 138.5, 138.6,
138.9, 141.4, 196.7; nmax(neat)/cm21 3032, 2874, 1676, 1602, 1452, 1068
(Calc. for C60H66O11S: C, 72.40; H, 6.69; Found: C, 72.28; H, 6.88%).
¶ Selected data for 6d: dH(200 MHz, CDCl3, J/Hz) 5.50 (d, 1 H, J 3.2), 7.14
(q, 1 H, J 7.0).
S
S
O
O
AcO
H
promoter
10a
9
BnO
BnO
BnO
BnO
+
ROH
–H+
O
O
H+
BnO
BnO
2
OR
S
S
O
O
∑ Selected data for 7d: white solid, mp 96–98 °C; [a]D 260.2 (c 0.8,
CHCl3); dH(200 MHz, CDCl3, J/Hz) 1.64–1.75 (m, 1 H, H-2ax), 2.22–2.30
(m, 1 H, H-2eq), 3.37–3.73 (m, 13 H), 4.15–4.20 (m, 1 H), 4.30 (d, 1 H, J
7.8), 4.39 (m, 1 H), 4.37–4.97 (m, 12 H), 7.20–7.34 (m, 30 H); dC(50 MHz,
CDCl3) 36.5, 57.0, 68.4, 69.2, 74.5, 74.7, 74.8, 74.9, 75.2, 75.6, 71.4, 73.4,
78.0, 78.1, 79.2, 82.2, 84.6, 100.4, 104.6, 127.5, 127.7, 127.8, 127.9, 128.0,
128.1, 128.3, 128.4, 138.1, 138.3, 138.4, 138.5 (Calc. for C55H60O10. C,
74.96; H, 6.87. Found: C, 74.54; H, 6.92%).
OH
OH
8
10b
Scheme 2
provides both anomers in pure form by careful control of the
reaction time. Glycosidation of the parent ketone 2 under acid
catalysis is more sluggish than that of the acetate 1, invariably
providing mixtures of the a and b anomers 8 (Scheme 2). Since
b-glycosidation of 1 is totally stereoselective we take this
evidence as an indication of a different reaction pathway
followed by 1 and 2. In the former case, owing to the higher
reactivity of the acetate, the developing positive charge induced
on 1 by the catalyst might be trapped by the acceptor before
ring-opening of the oxathiine, as shown in 9, allowing for a
b-stereospecific glycosidic linkage formation. Subsequent a–b
equilibration might proceed through an oxonium intermediate
10a analogous to that leading to product mixture in the
glycosidation of the ketone 10b.
Deprotection of the thiosubstituted glycosides 5a,c,d, to the
corresponding 2-deoxyglycosides 7a,c,d∑ is readily achieved by
desulfurisation with Raney-nickel4,7 (Scheme 1). Reaction
times and yield are reported in Table 1.
In conclusion these preliminary results clearly indicate that
the aceate 1 is a readily available and effective new donor for
the synthesis of 2-deoxy-b-O-glycosides and that the described
procedure might represent a competitive protocol for an
efficient a–b stereocontrol in the glycosidation reaction.
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Received in Liverpool, UK, 15th July 1997; 7/05338J
2292
Chem. Commun., 1997