Chain elongation of primary alcohols of carbohydrates

Article abstract of DOI:10.1016/j.tetlet.2004.08.037

The chain elongation of primary alcohol of saccharides (α-d-ribose, α-d-glucose, α-d-mannose) and a disaccharide (α-d-melibiose) has been achieved via a Mitsunobu reaction using bis(2,2,2-trifluoroethyl) malonate as nucleophile.

Full text of DOI:10.1016/j.tetlet.2004.08.037

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7465–7467
Chain elongation of primary alcohols of carbohydrates
*
´
Caroline Clavel, Veronique Barragan-Montero and Jean-Louis Montero
´
Laboratoire de Chimie Biomoleculaire, UMR 5032 (UM2, CNRS, Mayoly-Spindler), ERT 5–ENSCM, 8,
Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
Received 22 July 2004; revised 5 August 2004; accepted 6 August 2004
Abstract—The chain elongation of primary alcohol of saccharides (a-D-ribose, a-D-glucose, a-D-mannose) and a disaccharide
(a-D-melibiose) has been achieved via a Mitsunobu reaction using bis(2,2,2-trifluoroethyl) malonate as nucleophile.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
with the primary alcohol of a variety of carbohydrates.
To achieve our goal, it was necessary to prepare carbo-
hydrates with a free primary hydroxy group for subse-
quent three-carbon homologation.
The elongation of the primary alcohol of saccharides is
of chemical as well as biological interest. To take one
example, saccharides are natural ligands of lectins,
which are receptors present on the surface of cells. The
effect of homologation of a ligand-active moiety in the
interaction with the lectin can lead to a better recogni-
tion between the two entities.1 Few methods have been
proposed to prepare higher homologs: substitution of
a halogenated compound,2 oxidation of the terminal
hydroxymethyl group to an aldehyde followed by a
Grignard3–6 or a Wittig7 reaction.
Chain elongation was first achieved on a-D-mannose
(Scheme 1). Methyl-a-D-mannopyranoside 1 was used
to initiate the synthesis. It was first selectively protected
on the primary hydroxy with a 4-methoxytrityl group to
give 2. The secondary hydroxys were then protected
with benzyl groups (2–3). Compound 3 was then selec-
tively deprotected at C-6 with ceric ammonium nitrate
to afford the primary alcohol 4. Chain elongation on
compound 4 was carried out using different Mitsunobu
conditions. Optimal conditions for this reaction depend
upon the alcohol and nucleophile but two other para-
meters are also important: (a) the redox couple and (b)
the solvent. Since many redox combinations have found
selected use, we decided to run the reaction in toluene
In contrast, an abundant literature on the Mitsunobu
reaction can be found since 1967, when Mitsunobu
and Yamada published their original article.8–12 This
reaction is a versatile method to condense an alcohol
with an acidic compound using a redox couple, but up
to now, it has not been extended to the primary alcohol
of carbohydrates. Carbon–carbon bond formation by
the Mitsunobu reaction is limited to nucleophiles with
an acidic hydrogen. Malonates are in general not acidic
enough to be used in Mitsunobu reactions. In 2002,
mono- and dialkylation of bis(2,2,2-trifluoroethyl) malo-
nate under common Mitsunobu conditions was reported
by Takacs et al.13 As part of a study to synthesize higher
carbohydrate homologs, we now report the use of the
Mitsunobu reaction to condense this activated malonate
OH
MeOTrO
OH
OH
O
O
a
HO
HO
HO
HO
1
2
OCH3
OCH3
96%
b
OH
MeOTrO
OBn
O
OBn
O
BnO
BnO
c
BnO
BnO
4
3
OCH3
88%
Keywords: Chain elongation; Carbohydrates; Mitsunobu reaction;
OCH3
80%
Bis(2,2,2-trifluoroethyl) malonate; Primary alcohol.
*
Scheme 1. Reagents and conditions: (a) MeOTrCl, DMAP, pyridine;
(b) BnBr, KOH, 130°C; (c) CAN, CH3CN–H2O.
Corresponding author. Tel./fax: +33 467147290; e-mail: vbarragan@
univ-montp2.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.037

7466
C. Clavel et al. / Tetrahedron Letters 45 (2004) 7465–7467
Table 1. Reactions of the bis(2,2,2-trifluoroethyl)malonate with dif-
ferent sugars following conditions: (a) reported in Scheme 2
F CH CO C
CO CH CF
3
2
2
2
2
3
OH
CO CH CF
3
OBn
O
OBn
O
2
2
Starting material
Product
Yield
(%)
BnO
BnO
BnO
BnO
CO CH CF
3
2
2
5
4
OCH
OCH
3
3
a, b, c, d, e
F3CH2CO2C
CO2CH2CF3
O
a : 55%
b : 35%
c : 39%
d : 26%
e : 23%
Methyl
a-D-glucopyranoside
55
BnO
BnO
OBn
OCH3
6
Scheme 2. Reagents and conditions: (a) ADDP/PPh3/toluene (0.33M);
(b) same reagents (0.07M); (c) ADDP/PPh3/THF (0.33M); (d) same
reagents (0.07M); (e) DIAD/PPh3/toluene (0.33M).
F3CH2CO2C
AcO
CO2CH2CF3
O
AcO
using 1,10-(azodicarbonyl)dipiperidine and triphenyl-
phosphine (ADDP/PPh3) or diisopropyl azodicarboxyl-
ate and triphenylphosphine (DIAD/PPh3) as reported
in Scheme 2. The efficacy of each azodicarboxylate
( 2equiv) was compared in the presence of 2equiv of tri-
phenylphosphine and 1.2equiv of bis(2,2,2-trifluoro-
ethyl) malonate in toluene. Under these conditions, it
appeared that the combination ADDP/PPh3 led to a
55% yield compared to a 23% yield obtained with the
DIAD/PPh3 couple.
a-D-Melibiose
19
OAc
O
O
AcO
AcO
OAc
OAc
7
F3CH2CO2C
F3CH2CO2C
O
Methyl
a-D-ribofuranoside
50
OCH3
OAc OAc
8
Beside the redox couple, the solvent is a parameter to
consider for the Mitsunobu reactions.14 The majority
of the reactions are run in tetrahydrofuran solution,
but many other solvents can be used. We decided to
compare two solvents: toluene and tetrahydrofuran,
using two different concentrations of carbohydrate
(0.07 or 0.33M). In our case, it appeared that the higher
concentration in toluene led to better results than in
tetrahydrofuran (see Scheme 2).
group. Then, the chain elongation was carried out after
deprotection of the primary hydroxy, following the
procedure described above to afford compound 7
(Table 1).
In the case of pentose the C-3 to C-5 migration of the
acetyl group does not occur, and, for this reason, this
protecting group could be used. Compound 8 was
obtained starting from methyl a-D-ribofuranoside and
the chain elongation was carried out on a-D-ribofurano-
side as described for the hexose (Table 1).
Therefore, the redox couple ADDP/PPh3 and toluene
(0.33M) were selected to carry out the reactions on a
variety of carbohydrates (Table 1).15
The chain elongation reaction on another hexose, a-D-
glucose, was accomplished according to the results
obtained with a-D-mannose. Therefore, starting from
2. Conclusion
The homologation of primary alcohol of saccharides
(pentose and hexose) and a disaccharide (a-D-melibiose)
has been achieved via a Mitsunobu reaction using
bis(2,2,2-trifluoroethyl)malonate as nucleophile. The
ease of the synthesis make this method attractive to
obtain new saccharide homologs.
methyl-a-D-glucopyranoside the homolog
6
was
obtained in four steps, following exactly the same stra-
tegy as done previously.
In order to demonstrate the generality of the method, we
decided to apply this three-carbon homologation to a
dissacharide and to a pentose.
References and notes
In the case of the disaccharide, a-D-melibiose, it was
decided to use acetyl as protecting group. It is notewor-
thy that acetylating the secondary hydroxys instead of
benzylating them can lead to a C-4 to C-6 migration
of the acetyl group. For example, in the case of mannose
the migration effect decreased the yield of the Mitsun-
obu reaction by about 10% when acetylation was used
instead of benzylation. Transesterification reactions16
have been previously reported in the case of hexoses.17
However, for ease of the synthesis acetylation was the
method of choice for the synthesis with the disaccharide.
The protection of the secondary hydroxys was run
in one pot after tritylation of the primary hydroxy
1. Vidil, C.; Morere, A.; Garcia, M.; Barragan, V.; Ham-
daoui, B.; Rochefort, H.; Montero, J.-L. Eur. J. Org.
Chem. 1999, 447–450.
2. Benito, J. M.; Ortiz Mellet, C.; Garcia Fernandez, J. M.
Carbohydr. Res. 2000, 323, 218–225.
3. Ste˛powska, H.; Zamojski, A. Tetrahedron 1999, 55, 5519–
5538.
4. Grzesczyk, B.; Zamojski, A. Carbohydr. Res. 2001, 332,
225–234.
5. Ste˛powska, H.; Zamojski, A. Carbohydr. Res. 2001, 332,
429–438.
6. Kim, M.; Grzesczyk, B.; Zamojski, A. Tetrahedron Lett.
2002, 43, 1337–1340.

C. Clavel et al. / Tetrahedron Letters 45 (2004) 7465–7467
7467
7. Barragan, V.; Menger, F. M.; Caran, K.; Vidil, C.;
Morere, A.; Montero, J.-L. Chem. Commun. 2001, 85–
86.
8. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967,
40, 2380–2382.
9. Mitsunobu, O. Synthesis 1981, 1–28.
J4–5 = 9.3Hz, H4); 4.02 (dd, 1H, J2–1 = 1.9Hz,
J2–3 = 2.9Hz, H2); 4.11 (dd, 1H, J3–2 = 3.1Hz,
J3–4 = 9.2Hz, H3); 4.11 (dd, 1H, J7–6a = 5Hz, J7–6b
9.2Hz, H7); 4.72 (m, 4H, HCH – CF3); 4.84 (s, 2H,
=
2
H
(ABq, 2H,
CH (Bn)); 4.87 (d, 1H, J1–2 = 1.7Hz, H1); m0 = 4.96
2
mA = 4.93, mB = 4,99, Dm = 24.8Hz, JAB
=
10. Hughes, D. L. Org. React. 1992, 42, 335–636.
11. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127–
164.
12. Lawrence, S. Pharma Chem. 2002, 12–14.
13. Takacs, J. M.; Xu, Z.; Jiang, X.-T.; Leonov, A. P.;
Theriot, G. C. Org. Lett. 2002, 4, 3843–3845.
14. Dodge, J. A.; Jones, S. A. Recent Res. Dev. Org. Chem.
1997, 1, 273–283.
12.2Hz,
H
CH (Bn)); m0 = 5.06 (ABq, 2H, A = 4.90,
m
2
mB = 5.21, Dm = 121.8Hz, JAB = 11Hz, HCH (Bn)); 7.50–
7.62 (m, 15H, HPh).
2
13C NMR (100.62MHz, CDCl3) d (ppm):31.5 (1C, C6);
48.4 (1C, C7); 55.3 (1C, OCH3); 61.5 (q, 2C,
JC–F = 37.2Hz, CH2–CF3); 69.5 (1C, C5); 72.6, 73.4 and
75.7 (3C, CH2(Bn)); 75.1 (1C, C2); 78.7 (1C, C4); 80.5 (1C,
C3); 99.7 (1C, C1); 123.1 (q, 2C, JC–F = 276.9Hz, CF3);
127.3–128.9 (15C, CHPh); 138.7, 138.8 and 138.9 (3C,
CIVPh); 167.4 and 167.7 (2C, C8).
15. Experimental conditions (typical procedure): To a solu-
tion of 4 (765mg, 1.65mmol), bis(2,2,2-trifluoroethyl)
malonate (530mg, 1.98mmol) and PPh3 (866mg,
3.3mmol) in 5mL of toluene were added 2equiv of ADDP
(833mg, 3.3mmol) over 30min. After stirring 24h at rt,
the solvent was removed under vacuo and the crude
product was purified by column chromatography on silica
gel (petroleum ether, then petroleum ether/ethyl ether 85/
15) to give the homolog 5 as an oil.
NMR 19F (188.31MHz, CDCl3) d (ppm): ꢀ74,14 (dd,
JF–H = 8.5Hz). ESI+/MeOH) m/z: 713 [M+Na]+.
ESIꢀ/MeOH) m/z: 737 [MꢀH]ꢀ.
For the synthesis of bis(2,2,2-trifluoroethyl) malonate see
Ref. 13.
All compounds and homologs were characterized by
1H NMR, 13C NMR, 19F NMR and MS.
16. Shaikh, A.-A. G.; Sivaram, S. Chem. Rev. 1996, 951–
976.
17. Morere, A.; Menut, C.; Vidil, C.; Skaanderup, P.; Thor-
sen, J.; Roque, J.-P.; Montero, J.-L. Carbohydr. Res. 1997,
300, 175–178.
1H NMR (400.13MHz, CDCl3) d (ppm): 2.45 (ddd, 1H,
J6a–5 = 10Hz, J6a–6b = ꢀ14.4Hz, J6a–7 = 4.9Hz, H6a); 2.87
(ddd, 1H, J6b–5 = 2.6Hz, J6b–6a = ꢀ14.1Hz, J6b–7 = 9Hz,
H
6b); 3.51 (s, 3H, OCH3); 3.84 (td, 1H, J5–4
=
=
J5–6a = 9.7Hz, J5–6b = 2.6Hz, H5); 3.96 (t, 1H, J4–3