A new stereocontrolled access to β-D-mannopyranosides and 2-acetamido-2-deoxy-β-D-mannopyranosides starting from β-D-galactopyranosides

Article abstract of DOI:10.1016/S0040-4039(02)02232-3

A new stereocontrolled synthesis of β-D-mannopyranosides was defined relying on a high yielding sequence based on the following three key steps: (a) a stereospecific inversion at C-2 of β-D-galactopyranosides by an oxidation-reduction procedure; (b) a regiocontrolled formation of 4-deoxy-β-D-threo-hex-3-enopyranosides; (c) a regio- and stereocontrolled hydroboration-oxidation of the above enol ethers. The flexibility of this new method was demonstrated by its extension to the synthesis of 2-acetamido-2-deoxy-β-D-mannopyranosides and of an orthogonally protected β-D-mannopyranoside scaffold and, finally, by the transformation of lactose into the two biologically relevant disaccharides with primary structure β-D-Manp-(1→4)-D-Glc and β-D-ManNAcp-(1→4)-D-Glc.

Full text of DOI:10.1016/S0040-4039(02)02232-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8815–8818
A new stereocontrolled access to b-
2-acetamido-2-deoxy-b- -mannopyranosides starting from
b-
-galactopyranosides†,‡
D-mannopyranosides and
D
D
Emanuele Attolino, Giorgio Catelani* and Felicia D’Andrea
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita` degli Studi di Pisa, Via Bonanno, 33, I-56126 Pisa, Italy
Received 5 September 2002; revised 7 October 2002; accepted 8 October 2002
Abstract—A new stereocontrolled synthesis of b-
the following three key steps: (a) a stereospecific inversion at C-2 of b-
(b) a regiocontrolled formation of 4-deoxy-b- -threo-hex-3-enopyranosides; (c) a regio- and stereocontrolled hydroboration–oxi-
dation of the above enol ethers. The flexibility of this new method was demonstrated by its extension to the synthesis of
2-acetamido-2-deoxy-b- -mannopyranosides and of an orthogonally protected b- -mannopyranoside scaffold and, finally, by the
transformation of lactose into the two biologically relevant disaccharides with primary structure b- -Manp-(1“4)- -Glc and
b- -ManNAcp-(1“4)- -Glc. © 2002 Elsevier Science Ltd. All rights reserved.
D
-mannopyranosides was defined relying on a high yielding sequence based on
D
-galactopyranosides by an oxidation–reduction procedure;
D
D
D
D
D
D
D
Several naturally occurring complex oligosaccharide
structures contain as relevant component a b- -Manp
or a b- -ManNAcp unit. The former type of monosac-
charide is a common fragment of the core region of
N-linked glycoproteins, a class of glycoconjugates hav-
ing a fundamental role in intercellular signaling,2 while
the second one is largely present in capsular polysac-
charides and is involved in the immunological response
of either Gram positive or Gram negative bacteria.3
for synthetic chemists, despite the impressive number of
efforts in this direction.4 In the frame of an ongoing
project aimed at the chemical valorization of lactose,1
we have been interested in efficient methods for the
D
D
transformation of b-
mannopyranosides analogues,
involving the epimerization both at C-2 and C-4.
D
-galactopyranosides into b-
D-
a
procedure overall
Although the procedure based on a first epimerization
at C-4 followed by a second one at C-2 (Scheme 1,
route b) has been reported,5 we have not found any
example of the alternative possibility employing the
The stereocontrolled synthesis of these types of glyco-
sidic linkages remains, however, an important challenge
Scheme 1.
Keywords: b-
D
-mannopyranosides; 2-acetamido-2-deoxy-b-
D
-mannopyranosides; b-D-talopyranosides; epimerization; hydroboration; stereoselec-
tivity.
* Corresponding author. E-mail: giocate@farm.unipi.it
† Dedicated to the memory of Professor Serena Catalano.
‡ Part 17 of the series ‘Chemical Valorization of Milk-Derived Sugars’. For Part 16, see: Ref. 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02232-3

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E. Attolino et al. / Tetrahedron Letters 43 (2002) 8815–8818
picture and a single compound was obtained in high
yield16 having the new 4-OH group in a trans orienta-
tion with respect to the substituents to the two contigu-
ous carbon atoms.17
inverse epimerization sequence (Scheme 1, route a). We
present here a useful way leading to the above result
using three consecutive key steps: (a) a stereospecific
inversion at C-2 of b-D-galactopyranosides; (b) a regio-
controlled formation of 4-deoxy-b-D-threo-hex-3-
enopyranosides;6 (c) a regio- and stereocontrolled
hydroboration–oxidation of the above enol ethers
(Scheme 2).
The synthesis of orthogonally protected b-D-mannopy-
ranosides, such as 4c, is of great interest; this type of
compounds, in fact, were reported only recently18 in the
frame of some studies directed to the combinatorial
synthesis of bioactive peptidomimetics. The transforma-
tion of 1 (X=OMe) into 4c clearly elucidates the value
of the present approach, leading to the target com-
pound with an overall 46% yield in a sequence requir-
ing only two chromatographic purifications.
The C-2 epimerization was efficiently achieved applying
an oxidation–reduction sequence to the mixed acetals 1
having the sole OH-2 group in the free form.7 Although
the stereoselective C-2 epimerization of b-D-galactopy-
ranosides by oxidation–reduction has been reported,8
the choice of acetals 1 as selectively protected interme-
diates represents by far the most efficient entry to
A further extension of the synthetic scheme was
devised, taking advantage from the regioselective for-
b-
D
-talopyranosides in terms of chemical and stereo-
-talopyrano-
mation of 2-acetamido-2,4-dideoxy-b-
D-threo-hex-3-
chemical yields.9 The transformation of b-
D
enopyranosides 5a,b.6
side mixed diacetals analogous of 1 into compounds
2a–c, having the sole OH-4 group free, was achieved
with high yield through simple protecting group
manipulations.9
Also in this case, the hydroboration–oxidation of enol
ethers 5a,b led with complete chemo-, regio- and
stereoselectivity to the b-
D-manno configured com-
pounds 6a,b (Scheme 3).16,17
The enol ethers 3 were successfully obtained through a
recently reported method6 of simultaneous activation–
elimination of axial hydroxyl groups with NaH–sulfuryl
diimidazole (Im2SO2). In the specific case of 4-O-depro-
All final compounds 4a–c and 6a,b have never been
reported but their structure was easily established by
NMR analysis, characterized by a set of diagnostic
coupling constants [very small J1,2 (0–1.6 Hz) and large
J3,4 and J4,5 (9–9.4 Hz)] typical of a mannopyranoside
moiety and reported for a lot of analogues.5b,c,19
tected b-D-talopyranosides, this process leads with com-
plete regioselectivity to 4-deoxy-b-D-threo-hex-3-
enopyranosides (3a–c)12 owing to the stereoelectronic
assistance offered by the antiperiplanar axial elec-
tronegative C-2 substituent to the base-promoted
extraction of the axial C-3 hydrogen atom.
In conclusion, we have presented a new, efficient and
flexible method for the regio- and stereocontrolled
transformation of b-
D
-galactopyranosides into b-
D
-
-
The transformation of enol ethers 3 into the targets
mannopyranosides and
2-acetamido-2-deoxy-b-
D
b- -mannopyranosides 4 was easily performed by
D
mannopyranosides through the epimerization at C-4 of
-talopyranosides never reported in literature. The
hydroboration–oxidation with borane–dimethyl sulfide
complex (BMS). The expected regioselective attack of
the boron on the b-enolic carbon of enol ethers13 has
been also reported in the case of glycals14 and 4-deoxy-
hex-4-enopyranosides.15 In these reactions the stereo-
chemical outcome of borane addition is controlled by
steric factors directing the boron attack mostly or com-
pletely anti to the allylic substituent. Hydroboration of
3 gave results in full agreement with the previous
b-D
usefulness of the method has been exemplified by the
effective synthesis, starting from lactose, of biologically
relevant disaccharide derivatives with primary structure
b-
Glc, and by the synthesis of an orthogonally protected
b- -mannopyranoside scaffold. The use of the above
strategy for the preparation of other di- and oligosac-
charides containing b- -mannopyranoside units is
D
-Manp-(1“4)-
D
-Glc and b-
D
-ManNAcp-(1“4)-D-
D
D
Scheme 2. Reagents and conditions: (i) NaH, DMF, 0°C, then Im2SO2, −30°C, 3 h, 80–95%; (ii) BH3·SMe2, 2 h, then H2O2,
NaOH, 2 h, 82–90%.

E. Attolino et al. / Tetrahedron Letters 43 (2002) 8815–8818
8817
Scheme 3. Reagents and conditions: (i) BH3·SMe2, 2 h, then H2O2, NaOH, 2 h, 82–90%.
under investigation in our laboratory and will be pre-
sented in due course.
6/THF), the hydrolytic removal of the two acetonide
function (80% aq. AcOH) to give the triol 7 which was
submitted to
a
stannylidene acetal promoted p-
methoxybenzylation10 (Bu2SnO, toluene, reflux, then
PMBCl, Bu4NI, reflux) to the diol 8, that was finally
regioselectively methoxymethylated at OH-6 (MOMCl,
DIPEA/CH2Cl2) to give 2c with an overall yield of 70%.
Acknowledgements
This research was supported with funds of University
of Pisa in the frame of the national project COFIN
2002 (MIUR–Rome).
10. The regioselective opening at C-3 of the 3,4-O-stannyl-
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8818
E. Attolino et al. / Tetrahedron Letters 43 (2002) 8815–8818
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