Exo-glycals as useful tools for anomeric functionalization of sugars - Carbohydrate Chemistry: Chemical and Biological Approaches - page 102

Br Br

O O

O O

iorii

O O

R 1 Br

O O O O

5 6

S

O

R 1 =

c

a b d e

OMe NO 2

i60%

i60%
ii 33%

i62% i61% i60%

ii 60%

OMe

COOMe

OMe

Me 3 Si

f g h i

OMe

i47% ii 50% ii 0% ii 0%

Scheme 3 Suzuki (i) and Stille (ii) couplings. i: R 1 B(OH) 2 (1.5 to 2 eq.), K 2 CO 3 (2M) (2eq./eq.
boronic acid), PdCl 2 (PPh 3 ) 2 (5 mol%), TFP (30 mol%), DME, 85 1 C, 24 h. ii: Bu 3 SnR 1 (1.5 eq.),
Pd 2 dba 3 (5 mol%), TFP (30 mol%), toluene, 140 1 C, MW, 50 min.

2.1.2 C-C bond formation at C-1 of monobromo exo-glycals. With
some mono-substituted compound 6 in hand, a second cross-coupling
reaction was envisioned. Obviously, this second C-C bond formation was
more ecient giving only one disubstituted compound 9. Suzuki
couplings were carried out in DME at 85 1C for 24 h in the presence of
5 mol% of Pd(PPh 3 ) 4 , 2 equivalents of boronic acid and 4 equivalents of
(2M) K 2 CO 3 . Stille coupling reactions were achieved in toluene, with
2 equivalents of the organostannane, 30 mol% of trifurylphosphine and
5 mol% of Pd 2 dba 3 . A series of compounds 9 was prepared in excellent
yield under these conditions as shown in Scheme 4.
Using this approach, different isomers of di-substituted exo-glycals can
be prepared as stereochemically pure isomers by simply choosing the order
of introduction of the aromatic or heteroaromatic substituents (compare
9d and 9e in Scheme 4). Interesting exo-glycals with non-aromatic sub-
stituents can be obtained by Stille type coupling provided that this
substituent is not introduced first as it was sensitive to Suzuki conditions.
This easy access to gem di-substituted olefins with aromatics prompted
us to investigate some biological properties of them, on the basis of the
analogy of compounds 9 with ecient inhibitors of tubulin polymerization
like combretastatin, 18 iso-combretastatin 19 and phenstatin 20 (Fig. 1).
It was reasoned that the introduction of a sugar unit on the olefin
would serve as a modulator of solubility by removal of the protecting
groups on the one hand. On the other hand the protected sugar unit may
also modify the biological properties of the compounds by initiating
hydrophobic interaction within a postulated binding pocket in tubulin.
The 3,4,5-trimethoxyphenyl unit is a common feature of the model
molecules and this moiety was retained in our analogues. This residue was
introduced first under our classical reaction conditions by reaction of
3,4,5-trimethoxyphenylboronic acid with 5 in DME in the presence of TFP
and PdCl 2 (PPh 3 ) 2 . The corresponding monosubstituted derivative of Z
configuration 6f (Scheme 3) was obtained in 47% isolated yield. A second
aromatic moiety was then introduced by the same reaction to give the