C-glycosylation invented by Pr Lubineau’s team: a key-reaction for innovation in cosmetics - Carbohydrate Chemistry: Chemical and Biological Approaches - page 3

R 1 O O HO R 1

HO NaHCO 3

H 2 O
90°C

O O

R 3 R 3

+

HO CH 3

HO

H 3 C CH 3

OH

R 2

R 2

O

glucose: R 1 =H,R 2 =OH,R 3 =H

mannose: R 1 =OH,R 2 =H,R 3 =H

cellobiose: R 1 =H,R 2 =OH,R 3 = β -D-glucose

Scheme 1 The Lubineau reaction.

In compliance with this strong commitment, the known interest of
C-glycosyl derivatives as carbohydrates biomimetics 9 and the discovery of
a new process of C-glycosylation invented by Pr. Lubineau and his team 10
(Scheme 1) were instrumental in such strategy.
The new process, contrarily to other processes known to synthesize
C-glycosyl compounds, 11 is in perfect agreement with green chemistry
principles, notably avoiding the use of protecting groups and toxic re-
agents and solvents. It proceeds 10 via a Knoevenagel's reaction between
activated methylene and a naked aldose followed by a Michael-type
intramolecular addition and a retro-Claisen aldol condensation leading
to the b-C-glycosyl anomer (Scheme 2). The yield of the pure anomer b
reinforced our interest in this reaction in complete agreement with the
''biomimetic'' approach.

3 Synthesis of new eco-designed C -glycosyl derivatives
In order to study the potential of this reaction in our research for GAGs
biosynthesis activators, various C-glycosyl derivatives were synthesized
from different carbohydrate units and b-diketones as described in
Scheme 3.
Table 1 shows that the nature of the sugar has an impact on the re-
action yield with, for instance, a limited interest for arabinose as com-
pared to xylose, illustrating the importance of the stereochemistry.
Moreover, the choice of activated methylenes is also restrictive since only
the b-diketone with a simple methyl residue (2,4-pentanedione) gives
quantitative yields.
In our hands, malonates, malonamide, malononitrile, Meldrum's acid,
hexafluoroacetylaceton, 1,3-indanedione, ethyl cyanoacetate also failed to
lead to C-glycosyl products. However, collaborating with Pr. Lubineau's
team, 12 we succeeded in replacing the 2,4-pentanedione by diketones
bearing long alkyl chains as described in Scheme 4, but without quan-
titative yields.
End-products with a C-8 chain (total chain with n = 5) in particular are
obtained with 75% yields from D -glucose and 65% from D -maltose. As
depicted in Scheme 4, the diketonic reagent should necessarily be
symmetric to avoid the concomitant synthesis of a mixture of C-glycosyl
ketones of various chain lengths, inevitable with asymmetrical diketones.
Moreover, the synthesis of the C-maltosyl products clearly points out that
these disaccharides also show reactive in the Lubineau's reaction.