Synthesis of [18-C-6]-β3-(L)-DOPA, first β-amino acid with a crown-ether receptor side-chain

Article abstract of DOI:10.1016/S0040-4039(02)02035-X

Terminally protected Boc-β³-(L)-DOPA-OMe has been synthesized from (L)-DOPA by the Arndt-Eistert homologation procedure. Then, a first crown-ether derivative, Boc-[18-C-6]-β³-(L)-DOPA-OMe, has been obtained by bis-O-alkylation of the

Full text of DOI:10.1016/S0040-4039(02)02035-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8241–8244
Synthesis of [18-C-6]-b3-(L)-DOPA, first b-amino acid with a
crown-ether receptor side-chain
Anne Gaucher, Olivier Barbeau, Wahib Hamchaoui, Lucie Vandromme, Karen Wright,
Michel Wakselman and Jean-Paul Mazaleyrat*
SIRCOB, ESA CNRS 8086, Baˆt. Lavoisier, University of Versailles, F-78000 Versailles, France
Received 19 July 2002; accepted 18 September 2002
Abstract—Terminally protected Boc-b3-(L)-DOPA-OMe has been synthesized from (L)-DOPA by the Arndt–Eistert homologa-
tion procedure. Then, a first crown-ether derivative, Boc-[18-C-6]-b3-(L)-DOPA-OMe, has been obtained by bis-O-alkylation of
the catechol function with cyclization, using Cs2CO3 as base and pentaethyleneglycol ditosylate as alkylating agent, in DMF at
60°C. © 2002 Elsevier Science Ltd. All rights reserved.
In the past decade, an increasing amount of work has
viously, we have synthesized crown-carrier a,a-disubsti-
tuted a-amino-acids able to induce 310 helices,4 where
been devoted to the construction of molecular receptors
and devices based on peptidic frameworks.1 In that
the side chains of residues at i and i+3 positions of the
backbone are well superposed as in the case of the 314
field, the pioneering studies of Voyer et al.2 have high-
lighted the interest of synthetic a-amino acid derivatives
of (L)-DOPA, bearing a crown-ether receptor on their
side-chain, which can be easily assembled in structurally
well-defined nanometer-scale peptidic architectures of
bis-crown as well as polymeric crown compounds, in
view of preparation of peptide-based ion-selective
molecular receptors for alkali metal, ammonium and
di-ammonium ions, as well as artificial ion channels.
According to the well-documented ability of b-amino
acids to induce helical conformations of the backbone
of their peptide oligomers (314 or 2.512 helices),3 differ-
ent in nature and even more stable than those adopted
by peptides based on a-amino acids, we found it inter-
esting to introduce crown-ether receptors on the side-
chains of such b-amino acids, to investigate the
structure of their short-chain peptide oligomers and
that of their corresponding ‘sandwich’ complexes. Pre-
helices of b-amino acid oligomers: [20-C-6]-Bip possess-
ing an axially chiral 2,2%,6,6%-tetrasubstituted biphenyl
frame,5 and derivatives with a-carbon chirality, [15-C-
5]-a-Me-(L)-DOPA, [18-C-6]-a-Me-(L)-DOPA (Fig. 1),
[benzo-18-C-6]-a-Me-(L)-DOPA and [benzo-24-C-8]-a-
Me-(L)-DOPA.6 In the present communication, we
report the synthesis of terminally protected b3-(L)-
DOPA and of a first crown-ether derivative: [18-C-6]-
b3-(L)-DOPA (Fig. 1).
For their synthesis, we considered the classical Arndt–
Eistert homologation of either N-Boc or N-Fmoc pro-
tected a-amino acids, developed by Seebach et al.7
Application of this method to (L)-DOPA required the
selective protection of both the amino group and the
side chain OH groups of the catechol function. Thus,
H-(L)-DOPA-OH was first converted to H-(L)-DOPA-
Figure 1. Structure of the crown-carrier amino acids (S)-[20-C-6]Bip,5 [18-C-6]-a-Me-(L)-DOPA6 and [18-C-6]-b3-(L)-DOPA.
Keywords: b-amino acids; b-peptides; b3-(L)-DOPA; crown-ethers.
* Corresponding author. Fax: (33) 01 39 25 44 52; e-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02035-X

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A. Gaucher et al. / Tetrahedron Letters 43 (2002) 8241–8244
OMe·HCl8,9 and then to Boc-(L)-DOPA-OMe 19,10
aqueous NaOH in MeOH/THF at room temperature
followed by acidification, gave pure Boc-(L)-
DOPA[OBn]2-OH 315 in 87% yield (crude), which was
activated to the mixed anhydride Boc-(L)-
DOPA[OBn]2-OCOOEt by treatment with ethyl chloro-
formate and triethylamine in THF at −10°C for 15 min.
Subsequent reaction with diazomethane led to the dia-
zoketone Boc-(L)-DOPA[OBn]2-CHN2 415 in 80%
yield. Wolff rearrangement16 of 4 upon treatment by
silver benzoate and triethylamine in MeOH with the
exclusion of light,7 afforded the fully protected b-amino
ester Boc-b3-(L)-DOPA[OBn]2-OMe 515 in 63% yield.
(Fig. 2) by described procedures.8–12
Two alternative pathways were then applied, in which
the crown-ether part of the molecule was introduced
either at the first stage of the synthesis or at the last
one. In path A, the catechol function of 1 was treated
with potassium carbonate, sodium iodide and a large
excess of benzyl bromide in refluxing acetone,13,14 to
afford the fully protected amino acid Boc-(L)-
DOPA[OBn]2-OMe 215 in 85% yield after chromatogra-
phy. Saponification of the ester function with 1N
Figure 2. Synthesis of Boc-[18-C-6]-b3-(L)-DOPA-OMe I: (i) SOCl2, MeOH, 0°C to rt; (ii) Boc2O, NaHCO3, H2O/THF, rt; (iii)
BnBr, K2CO3, NaI, acetone, 50°C; (iv) NaOH, MeOH/THF, rt; (v) 1. ClCOOEt, TEA, THF, −10°C, 15 min, 2. CH2N2, Et2O,
0°C to rt, 18 h; (vi) AgOBz, TEA, THF, −25°C to rt; (vii) H2, 10% Pd/C, MeOH, 3.4 atm, rt; (viii) Cs2CO3, TsOCH2–
(CH2OCH2)4–CH2OTs, DMF, 60°C.

A. Gaucher et al. / Tetrahedron Letters 43 (2002) 8241–8244
8243
Finally, deprotection of the catechol function of 5 by
hydrogenolysis with H2/Pd–C (Parr apparatus), gave
the desired Boc-b3-(L)-DOPA-OMe 615 in 99% yield.
Applying similar experimental conditions as those pre-
viously reported by Voyer et al.2a,d and then by us for
the preparation of both [20-C-6]-Bip5 and [18-C-6]-a-
Me-(L)-DOPA,6 the terminally protected amino acid 6
was reacted with cesium carbonate in methanol at
45°C. The solution was evaporated in vacuo, the
residue was solubilized in DMF and the solution was
again evaporated in vacuo at 45°C in order to com-
pletely remove methanol. To the so-obtained di-cesium
salt of 6 was added DMF and the resulting diluted
solution (0.1 mol/l) was reacted at 60°C with a DMF
solution (0.25 mol/l) of pentaethylene glycol ditosylate
(1.1 equiv. mol/mol) which was added dropwise during
a 1 h period. The reaction mixture was stirred at 60°C
for 18 h, DMF was evaporated in vacuo, the crude
product was extracted and then purified by chromatog-
raphy as previously described,6 to afford Boc-[18-C-6]-
b3-(L)-DOPA-OMe I15 in 44% yield.
2. (a) Voyer, N. J. Am. Chem. Soc. 1991, 113, 1818–1821;
(b) Voyer, N.; Roby, J. Tetrahedron Lett. 1991, 32,
331–334; (c) Voyer, N.; Descheˆnes, D.; Bernier, J.; Roby,
J. J. Chem. Soc., Chem. Commun. 1992, 134–136; (d)
Voyer, N.; Roby, J.; Descheˆnes, D.; Bernier, J. Supramol.
Chem. 1995, 5, 61–69; (e) Voyer, N.; Gue´rin, B. J. Chem.
Soc., Chem. Commun. 1997, 2329–2330; (f) Voyer, N.;
Potvin, L.; Rousseau, E. J. Chem. Soc., Perkin Trans. 2
1997, 1469–1471; (g) Meillon, J.-C.; Voyer, N. Angew.
Chem., Int. Ed. Engl. 1997, 36, 967–969; (h) Biron, E.;
Voyer, N.; Meillon, J.-C.; Cormier, M.-E.; Auger, M.
Biopolymers 2000, 55, 364–372; (i) Meillon, N.; Voyer,
J.-C.; Biron, E.; Sanschagrin, F.; Stoddart, J. F. Angew.
Chem., Int. Ed. Engl. 2000, 39, 143–145.
3. For some reviews on b-peptides, see: (a) Seebach, D.;
Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997,
2015–2022; (b) Gellman, S. H. Acc. Chem. Res. 1998, 31,
173–180; (c) DeGrado, W. F.; Schneider, J. P.; Hamuro,
Y. J. Peptide Res. 1999, 54, 206–217; (d) Gademann, K.;
Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999,
6, 905–925; (e) DeGrado, W. F.; Schneider, J. P.;
Hamuro, Y. J. Peptide Res. 1999, 54, 206–217; (f) Cheng,
R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
101, 3219–3232.
We also investigated a second route (path B) in which
the N-protected crown-carrier a-amino ester Boc-[18-C-
6]-(L)-DOPA-OMe 72d and then its N-protected a-
amino acid analogue Boc-[18-C-6]-(L)-DOPA-OH 82d
were first prepared from 1, allowing the suppression of
the two steps of protection/deprotection of the catechol
function required in path A. However, when the Arndt–
Eistert homologation was applied to compound 8 under
the same experimental conditions as above, the result-
ing samples of the diazoketone Boc-[18-C-6]-(L)-
DOPA-CHN2 9 and then of the rearranged final
N-protected b3-amino ester I, were of a poor quality
even after purification. Furthermore, the unidentified
impurities observed by NMR were found to be impossi-
ble to remove by standard chromatography.
4. For some reviews on a,a-disubstituted a-amino acids and
their peptides, see: (a) Karle, I. L. Acc. Chem. Res. 1999,
32, 693–701; (b) Benedetti, E. Biopolymers 1996, 40, 3–44;
(c) Karle, I. L. Biopolymers 1996, 40, 157–180; (d)
Toniolo, C.; Crisma, M.; Formaggio, F.; Benedetti, E.;
Santini, A.; Iacovino, R.; Saviano, M.; Di Blasio, B.;
Pedone, C.; Kamphuis, J. Biopolymers 1996, 40, 519–522;
(e) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.
Biopolymers 2001, 60, 396–419.
&
5. (a) Mazaleyrat, J. P.; Gaucher, A.; Goubard, Y.; Savrda,
J.; Wakselman, M. Tetrahedron Lett. 1997, 38, 2091–
2094; (b) Mazaleyrat, J.-P.; Goubard, Y.; Azzini, M.-V.;
Wakselman, M.; Crisma, M.; Formaggio, F.; Toniolo, C.
Peptides 2000, Martinez, J.; Fehrentz, J.-A., Eds.; EDK:
Paris, France, 2001; pp. 185–186; (c) Mazaleyrat, J.-P.;
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1232–1247.
In summary, it appears that route A, although involv-
ing more steps, should be preferred to route B in which
careful HPLC would probably be necessary for purifi-
cation. The availability of Boc-b3-(L)-DOPA-OMe 6
itself only in route A also presents the advantage of
allowing the convergent synthesis of a variety of ana-
logues with different crown-ethers or other receptors
anchored on the side-chain of b3-(L)-DOPA by taking
advantage of the catechol function. The synthesis of
such a series of compounds and their corresponding
b-peptide oligomers is under way to examine their
conformational behaviour as well as their complexing
abilities. As emphasized earlier, stable helical secondary
structures are expected in short-chain b-peptides involv-
ing such crown-carrier b3-(L)-DOPA residues, with the
opportunity for cooperative binding.
6. Wright, K.; Melandri, F.; Cannizzo, C.; Wakselman, M.;
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Mp 135°C {lit.9 Mp 133–135°C. lit.10 Mp 140–141°C}.
[h]D25=+7 (c 1.0; MeOH) {lit.9 [h]2D6=+7.6 (c 1.2;
MeOH)}. 2: Mp 112°C. [h]2D5=+42 (c 0.5; CH2Cl2). 3: Mp
120°C {lit.9 Mp 105–107°C. lit.12 Mp 139–141°C}. [h]2D5=
+14 (c 0.4; MeOH) {lit.9 [h]2D5=+14.2 (c 1; MeOH)}. 4:
Mp 127°C. [h]2D5=+19 (c 0.5; MeOH). 5: Mp 122°C.
[h]2D5=−14 (c 0.4; MeOH). 6: [h]2D5=−22 (c 0.1; MeOH).
7: [h]2D5=+3 (c 1.2; MeOH) {lit.2d [h]2D3=+5.5 (c 1;
MeOH)}. 8: [h]D25=+11 (c 1.0; MeOH) {lit.2d [h]2D3=+15.5
(c 1; MeOH)}. I: Mp 116°C. [h]2D5=−11 (c 0.25; MeOH).
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13. In our hands, the use of acetone as solvent14 instead of
ethanol9–12 or methanol resulted in a much higher yield
and a cleaner reaction.
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15. All new compounds gave satisfactory analytical data (1H,
13C NMR, C,H,N analysis and/or ESI+/MS). Experimen-
tal details of synthesis will be given further in a full
account of this study. Selected data are reported below. 1: