Solution and solid phase synthesis of hetarylene-carbopeptoids. A new type of peptidomimetics

Article abstract of DOI:10.1016/S0040-4039(00)02266-8

Ready access to a new class of peptidomimetics has been demonstrated by the synthesis of hetarylene-carbopeptoids using hydroxyalkylfuran-aminoacids 7 as novel scaffold.

Full text of DOI:10.1016/S0040-4039(00)02266-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1283–1285
Solution and solid phase synthesis of hetarylene-carbopeptoids. A
new type of peptidomimetics
A. J. Moreno-Vargas, J. G. Fern a´ ndez-Bola n˜ os, J. Fuentes and I. Robina*
Departamento Qu ´ı mica Org a´ nica, Facultad Qu ´ı mica, Universidad Sevilla, Apartado 553, E-41071 Seville, Spain
Received 30 September 2000; accepted 8 December 2000
Abstract—Ready access to a new class of peptidomimetics has been demonstrated by the synthesis of hetarylene-carbopeptoids
using a hydroxyalkylfuran-aminoacid 7 as a novel scaffold. © 2001 Elsevier Science Ltd. All rights reserved.
1
Peptides and proteins are logical targets for mimicry
due to their fundamental role in biological processes
and because of the pharmacological limitations of natu-
used to make it, and a 5-alkylfuran moiety, the alkyl
group (j) of which can be varied on changing the acyl
acetate employed in the condensation with the starting
2
ral bioactive peptides. Potentially useful peptidomimet-
ics should resist in vivo hydrolysis and present some
COOEt
Me
COOH
Me
3
conformational bias. With these goals in mind, Gell-
OH
OR
4
i, ii
man et al. have prepared peptides from rigidified cyclic
HO
O
1
RO
5
O
b-aminoacids. Nicolaou et al. first introduced the use
HO OH
OR OR
of sugars as a means to increase the rigidity of pepti-
domimetics, and introduced the name of ‘carbopeptoid’
for such oligomers that are peptide-bond linked carbo-
hydrates. Some of them have interesting biological
iii 2, R = H
3, R = Ac
iv, v
(
1 step)
ref. 9
COOEt
Me
Glucose
OH
HO OH
6
properties, including HIV replication inhibition.
N3
O
4
vi
i, ii
Aminoglycoside antibiotic mimetics, made from N-
7
acetylneuraminic acid, have been reported. On their
COOEt
Me
COOH
8
hand, Fleet et al. have reported peptidomimetics
OH
OH
adopting interesting secondary structures because of the
carbohydrate-derived tetrahydrofuran systems they
contain.
H N
2
O
5
N3
Me
O
HO OH
i, viii
O
H
OH 6
vii
COOH
Searching for new molecules that can be assembled
with themselves and/or other aminoacids using well
established combinatorial techniques, we propose a new
scaffold Aij (Fig. 1) which contains a polyol fragment
OH
HO OH
H N
2
O
7
Me
(
i) whose length and chirality are given by the aldose
ix, x, xi
COOH
Me
OH
HO OH
Fmoc N
O
8
Chirality
H
COOH
R
Rigidity
Flexibility
Aldose
+
H2N
O
Scheme 1. Building blocks. Reagents and conditions: (i)
O
O
+
OH n
NaOH 1 M, EtOH, 60°C, 3 h; (ii) IR-120 (H ), MeOH (80%
Hydrophilicity
R
OEt
Lipophilicity
for 2, 90% for 6, two steps); (iii) Ac O, Py (quant.); (iv) TsCl,
2
Py, −15°C, 2 h (57%); (v) NaN , DMF, 110°C, 2.5 h (70%);
3
Figure 1. Scaffold Aij.
(
vi) H , Pd/C, EtOH, 15 min (98%); (vii) H , Pd/C, MeOH, 2
2
2
h (60%); (viii), 1 M HCl (80% for two steps); (ix) TMSCl, Py,
1 h; (x) FmocCl, 1 h; (xi) H O 2 h (95% for three steps).
*
0
Corresponding author. E-mail: robina@cica.es
,
2
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02266-8

1
284
A. J. Moreno-Vargas et al. / Tetrahedron Letters 42 (2001) 1283–1285
9
aldose. We now describe the synthesis of one member
of the sub-library Aij (i, n=3, configuration: -arabino)
COOEt
Me
OH
D
and demonstrate that it can be combined to generate
oligomers by applying either solution or solid phase
processes.
H N
2
O
OH OH 5
a
COOEt
Me
O
OH
The polyhydroxy and alkylfuran moieties make these
compounds attractive, as complex biochemical pro-
cesses involve molecular recognition based on polar
OH
N
H
O
OH OH
R´
O
Me
10
(
e.g. hydrogen bonds) and hydrophobic interactions.
OH OH
13: R´= N3
1
b
4: R´= NH2
The synthesis of the building blocks (Scheme 1) starts
COOEt
Me
c
9
from 1. Regioselective tosylation, followed by SN2
O
OR
displacement with NaN gave the azidoester 4. Subse-
3
O
OR
N
H
O
quent hydrogenation furnished 5. Hydrolysis of esters 1
and 4 provided carboxylic acids 2 and 6, respectively.
Reduction of the azide 6 delivered aminoacid 7 which
was N-protected as the Fmoc derivative 8. This
required protection of the polyol as a polysilyl ether in
order to avoid formation of carbonates (a regioselective
direct reaction gives complex mixtures and a low yield
OR OR
OR
OR OR
N
H
O
Me
OR OR
1
1
5: R = Ac
6: R = H
N3
O
Me
d
Scheme 3. Tail elongation. Reagents and conditions: (a)
PyBOP, DIPEA, DMF, 1 equiv. of 6, 45 min (62%); (b) H2,
Pd/C, EtOH, 30 min (95%); (c) (i) a, (ii) Ac O, Py, 12 h (60%
1
1
2
for 8). Koole’s procedure (TMSCl/py, then FmocCl/
for two steps); (d) NaOMe, MeOH (quant.).
py, then H O) led to 8 in 95% overall yield.
2
The strategy of head elongation (Scheme 2) is based on
the condensation of acid 2 with the aminoester 5 under
PyBOP (benzotriazolyloxy-trispyrrolidino phospho-
nium hexafluorophosphate) and DIPEA (N,N-diiso-
1
2
14
Mukaiyama conditions. This gave, after acetylation,
the dimeric derivative 9. The latter was easily
hydrolyzed into 10 and coupled again with the
propylethylamine) as activating reagents. After 45 min
the dimer 13 was isolated in 70% yield. Reduction of
the azide and a subsequent coupling reaction gave the
corresponding trimer that was purified in the per-acety-
13
aminoester 5 to give the trimer 11. When using a
mixture of DCM/DMF, the protected per-acetate 3 and
5, the yield was increased.
15
lated form 15 in 60% yield.
For the tail elongation (Scheme 3), the coupling of
unprotected 5 and 6 was carried out in DMF with
In order to demonstrate the viability of the use of solid
phase techniques for incorporating our scaffold Aij into
oligomers, we envisaged the synthesis of the pseudotet-
rapeptide 21 on a solid support (Scheme 4). We have
used the Fmoc strategy and the HMBA-AM resin in
COOH
OR
RO
O
Me
1
6
which the linker is the 4-hydroxymethyl benzoic acid.
OR OR
2: R = H
The couplings were accomplished without protection of
the OH groups of the amino acid 8. The commercially
available Fmoc-glycine was attached to the OH resin
3: R = Ac
a, for R = H
b, for R = Ac
R´
Me
O
OR
17
using 2,6-dichlorobenzoyl chloride and pyridine. This
OR
N
H
O
offers a double advantage: it favours the anchoring to
the HO resin by avoiding competitive reactions with the
free OH groups of 8, and facilitates the final cleavage of
the oligomer from the resin. Subsequent treatment with
piperidine gave the solid-supported amine 18. The
Fmoc-aminoacid 8 was then coupled by treatment with
PyBOP and DIPEA in DMF, affording the immobi-
lized dimer 19. The process was repeated twice to
obtain the polymer-bound compound 20 that was
removed from the solid support with 1 M NaOH and
THF as co-solvent to assist swelling of the resin. The
OR OR
: R = Ac, R´ = COOEt
0: R = Ac, R´ = COOH
RO
O
Me
9
1
OR OR
c
d
COOEt
Me
O
OR
O
OR
N
H
O
OR OR
OR
OR OR
N
H
O
Me
OR OR
RO
O
Me
1
1
1: R = Ac
2: R = H
e
18
aminoacid 21 presents high water solubility. This
method could provide a library of oligomers with high
bioavailability.
Scheme 2. Head elongation. Reagents and conditions: (a) (i) 2
equiv. Ph P, 2 equiv. of PyS-SPy, DMF, 2 equiv. of 5, 12 h,
3
(
ii) Ac O, Py, 12 h (54% for two steps); (b) (i) 2 equiv. of
2
Ph P, 2 equiv. PyS-SPy, DCM:DMF (3:1), 1 equiv. of 5, 6 h,
3
(
ii) Ac O, Py, 12 h (74% for two steps); (c) (i) 1 M NaOH,
In conclusion, we have synthesized a new class of
compounds that represent new leads for combinatorial
chemistry in glycopeptidomimetic design. The ease of
preparation, their structural diversity with respect to
2
+
EtOH, 10 h, 60°C, (ii) IR-120 (H ), MeOH, (iii) Ac O, Py
2
(
89% for three steps); (d) b (60% for two steps); (e) NaOMe,
MeOH (quant.).

A. J. Moreno-Vargas et al. / Tetrahedron Letters 42 (2001) 1283–1285
1285
O
i, ii
H N
2
OH
O
18
17
iii, ii
O
O
O
OH
N
H
O
H N
2
Me
19
...twice (iii, ii)
OH
O
OH OH
O
O
OH
N
H
O
N
H
O
Me 2
iv, v
OH OH
H N
2
O
Me
20
OH OH
O
O
OH
N
H
COOH
OH
OH OH
N
O
Me 2
H
OH OH
1
H N
2
O
Me
2
Scheme 4. Solid phase synthesis: Fmoc strategy. Reagents and conditions: (i) 2,6-dichlorobenzoyl chloride, py, DMF, Fmoc-Gly-
OH; (ii) 20% PIP/DMF; (iii) PyBOP, DIPEA, DMF, 1 equiv. of 8; (iv) 1 M, NaOH, THF; (v) 1 M AcOH (60% overall).
functionality and stereochemistry and their stability
may lead to new bioactive compounds.
7. (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C.-H.
J. Am. Chem. Soc. 1996, 118, 10150–10155; (b)
Ramamoorthy, P. S.; Gervay, J. J. Org. Chem. 1997, 62,
7801–7805.
Acknowledgements
8. Smith, M. D.; Fleet, G. W. J. J. Peptide Sci. 1999, 5, 425
and references cited therein.
9. Garc ´ı a Gonz a´ lez, F.; G o´ mez S a´ nchez, A. Adv. Carbo-
hydr. Chem. 1965, 20, 303.
We thank Dr. Corinne Kay (Glaxo Wellcome Cam-
bridge Laboratory) for her valuable advice and help in
the performance of the solid phase synthesis, Professor
Pierre Vogel (University of Lausanne) for helpful dis-
cussions, the Direcci o´ n General de Investigaci o´ n Cien-
t ´ı fica y T e´ cnica of Spain (Grant No PB 97-0730) and
Junta de Andaluc ´ı a (FQM 134) for financial support,
and the University of Seville for a fellowship to A.J.M.-
V. This work is part of the European COST D13
Program, working group COST D13/0001/98.
1
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C
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