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been included in such oligomers.
39b,44
It was interesting to examine the
behaviour of oligomers derived from the above building blocks 41 and
43. These oligomers feature an N,O-acetal functionality and a spirocyclic
disubstitution at the b-carbon of the backbone, a new arrangement not
yet reported in the field of b-peptides.
Using a diisopropylidene D-mannofuranose template, the b amino
acids building blocks using N-Cbz protection 41 and 43 were prepared
and coupled to each other using HATU and DIPEA to obtain the dimer 46
in 70% yield. This compound was then transformed into two other
building blocks by removal of the Cbz group on the one hand (H
2
, Pd/C)
and of the ester group on the other hand (K
2
CO
3
, MeOH/H
2
O). Coupling
of these two building blocks gave the tetramer 47 in 47% yield. This
compound was further elaborated to the corresponding carboxylic acid,
and coupled with the corresponding amine of dimer 46 under the same
conditions to afford the hexamer 48 in 50% yield (Scheme 13).
From spectroscopic data, it was found that tetramer 47 and hexamer 48
adopt a characteristic secondary structure. NMR analysis was less in-
formative than that of more traditional b-peptide chains because of the
absence of CH(b), but together with IR gave evidence of the existence of a
defined solution conformation stabilized by H-bonding. DMSO NMR
titration and constrained MD simulations suggested the presence of two
consecutives C8 turns. The CD curves were also in agreement with helices
that display eight-membered hydrogen bonds.
The cyclization of tetramer 47 and hexamer 48 has been performed by
the classical sequence used for their construction, i.e. removal of the
ester and the Cbz group followed by activation of the carboxylic acid
using HATU and DIEA in DMF as a 3.6 mM solution. This sequence
R
H
COOMe
R
O
O
O
H
NH
2
COOMe
R
O
COOMe
O
HN
O
O
O
H
O
R
O
HATU
HN
O
H
O
41
O
O
R
HN
O
DIPEA
DMF, 18 h, 70%
O
R
COOH
O
NHCbz
O
H
O
NHCbz
H
O
H
NHCbz
R
O
O
O
O
O
H
O
R
O
H
O
46
47
43
O
R
O
H
R=
CbzHN
O
O
O
O
COOMe
H
O
O
O
HN
O
R
N
H
R
O
O
O
O
O
H
O
O
H
NH
O
O
H
O
H
R
O
O
O
R
O
R
H
H
O
48
Scheme 13 Sugar anomeric
b
amino acid oligomers.
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