(S)-Histidine: The ideal precursor for a novel family of chiral aminoacid and peptidic ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2005.12.090

(S)-Histidine is shown to be a powerful chiral precursor for the construction of a new series of imidazolium-containing chiral ionic liquids, in which the chiral bifunctional unit of the aminoacid remains unchanged. These ionic materials can be used as building blocks for the synthesis of peptidic ionic liquids.

Full text of DOI:10.1016/j.tetlet.2005.12.090

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1245–1248
(
S)-Histidine: the ideal precursor for a novel family of
chiral aminoacid and peptidic ionic liquids
a,
b
a
*
Fr e´ d e´ ric Guillen, Delphine Br e´ geon and Jean-Christophe Plaquevent
a
UMR-CNRS 6014 de l’IRCOF, Universit e´ de Rouen, rue Tesni e` re, F-76821 Mont-Saint-Aignan Cedex, France
b
UMR-CNRS 6507 LCMT, ENSICAEN, Universit e´ de Caen, 6 bd du Mar e´ chal Juin, F-14050 Caen, France
Received 16 November 2005; revised 12 December 2005; accepted 16 December 2005
Abstract—(S)-Histidine is shown to be a powerful chiral precursor for the construction of a new series of imidazolium-containing
chiral ionic liquids, in which the chiral bifunctional unit of the aminoacid remains unchanged. These ionic materials can be used as
building blocks for the synthesis of peptidic ionic liquids.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The search for new solvents and materials based on chi-
ral ionic liquids is a topic of increasing importance, since
numerous applications including asymmetric synthesis,
chiral chromatography, stereoselective polymerizations,
and NMR chiral discrimination have been recently
In connection with our insights about peptide synthesis
1
0
in ionic liquids, we envisioned (S)-histidine, a commer-
cially available natural aminoacid, as a key chiral start-
ing material for the elaboration of dissymmetric
imidazolium moieties by direct modification of the side
chain, thus leaving free the aminoacid function of the
1
described in the literature. This research topic also cons-
titutes a new creative area for organic chemists since
4
,11
obtained chiral ionic liquids (Fig. 1).
Thus, usual
‘
tailor made’ structures can be imagined and synthesized
aminoacid chemistry can be performed on the function-
alized ionic liquid. During the course of this study, Chan
et al. described the use of an achiral imidazolium salt as
for various purposes, such as chiral solvents, task-
specific ionic liquids, and immobilized catalyst. As an
example, some of us recently described a new series of
compounds, which exhibited both properties of ionic
1
2
a support for peptide synthesis.
2
liquids and of chiral liquid crystals.
In order to selectively alkylate both N-positions of the
imidazole ring while leaving the primary amine function
untouched, we chose to rely on a reported procedure,
which has been previously used to alkylate either the
For the construction of chiral ionic liquids, one of the
most prominent series of starting material taken from
the chiral pool is that of a-aminoacids, which are readily
available at low cost and offer interesting molecular
diversity from which could be built a large variety of
structures. Various chiral ionic liquids were previously
built starting from a-aminoacids. Although of power-
ful synthetic utility, none of the strategies used led to
chiral ionic liquids in which the aminoacid bifunctional
unit remains intact, the aminoacid being either trans-
formed or used as an ionic part of the salt.
1
3
14
N-1 or the N-3 (via the temporary protection of N-
1
3
1) position of histidine. As reported by Cohen, treat-
ment of the histidine methyl ester dihydrochloride with
carbonyldiimidazole in DMF afforded the cyclic urea 1
as a white crystalline solid in a good yield. However,
the reported procedure requires quite a large amount
of DMF that has to be evaporated off at the end of
3
–9
CO PG1
2
CO H
2
R1 N +
HN
N
HN
R2
PG2
N
NH2
X-
Keywords: Histidine; Aminoacid; Peptide; Chiral ionic liquid;
Imidazolium.
chiral bifunctional ionic liquid
imidazole chiral bifunctional
ring part
*
Corresponding author. Tel.: +33 2 35 52 24 65; fax: +33 2 35 52 29
1; e-mail: frederic.guillen@univ-rouen.fr
7
Figure 1. Chiral ionic liquids starting from (S)-histidine.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.090

1246
F. Guillen et al. / Tetrahedron Letters 47 (2006) 1245–1248
CO Me
2
CO Me
CO Me
1.nBuBr, neat
MeI
2
DIEA, tBuOH
2
N +
1
N
I-
N
N
NHBoc
o
o
4
0 C, 16h
N
NH
80 C, 3h
N
HN
OtBu
O
2. LiNTf2, KPF6
or NaBF4
X-
Bu
97%
69%
O
2
3
4
4
4
a X = NTf , 90%
2
b X = PF , 83%
6
c X = BF , 65%
4
Scheme 1. Synthesis of bis-protected histidinium salts.
the reaction. As the only byproduct of the reaction is
imidazole hydrochloride, which can (despite its rather
high melting point of 158–161 ꢁC) be considered as the
prototype of lower melting imidazolium salts, we rea-
soned that the reaction could be run without solvent
by mixing the two solid compounds with heating, rely-
ing on the in situ generated salt to obtain a homo-
geneous reaction mixture. We were delighted to see
that, upon heating a mixture of carbonyldiimidazole
and histidine methyl ester dihydrochloride with vigorous
mechanical stirring, a viscous liquid was obtained in a
few minutes at temperatures as low as 80 ꢁC (Eq. 1).
After hydrolysis and extraction with dichloromethane,
the expected cyclic urea 1 was obtained in good yield
and excellent chemical purity after simple washing with
2 was then opened by tert-butanol in the presence of
diisopropylethylamine, to give the Boc-protected N(1)-
1
3,16
alkylated histidine methyl ester 3.
Alkylation of 3
proceeded smoothly with n-iodobutane in acetonitrile
or, more conveniently, with neat n-bromobutane to give
the desired new chiral imidazolium salts. This strategy
allows inversion of the substitution pattern of the imid-
azolium ring by simply inverting the alkylation steps.
The resulting hygroscopic halide salts were immediately
engaged in an anion exchange reaction with lithium
1
7
bistriflimide,
potassium hexafluorophosphate, or
sodium tetrafluoroborate (Scheme 1). The resulting
1
8
liquid salts could be purified by flash column chroma-
tography on silica gel.
1
5
diethylether. It should be noted that, although the
reaction temperature is much lower than any of the reac-
tant or product’s melting point, the crude reaction mix-
ture is a homogeneous viscous liquid.
As these new species pertain to both aminoacid and
ionic liquid chemistry, we propose a naming system
based on aminoacid and peptide nomenclature, where
the ionic histidine-based imidazolium is represented as
an ionic liquid, that is with both anion and cation in
brackets. The imidazolium substituents (namely methyl
and butyl) have to be represented by their initial letter
CO Me
2
CO Me
2
carbonyldiimidazole
N
N
N
NH
NH NH . 2 HCl
2
(the N-1 substituent before the N-3 substituent) in the
O
cationic part. For instance, ionic liquid 4a will be named
ð1Þ
1
Boc-[MBHis][NTf ]-OMe.
2
o
DMF, 70 C, 3h
74%
82%
o
no solvent, 80 C, 30 min
The most interesting term of this series, namely 4a
o
no solvent, 100 C, 10 min 77%
(X = NTf ) was conveniently transformed into various
2
ionic structures by means of typical methods in amino-
acid chemistry (Scheme 2). Complete deprotection by
aqueous HCl quantitatively afforded the hydrosoluble
aminoacid hydrochloride 5. Selective deprotection was
performed either by hydrolysis of 4a with HCl in anhy-
Alkylation of 1 with methyl iodide in acetonitrile pro-
ceeded smoothly to give the corresponding salt 2 in high
yield as a crystalline, high melting solid. The cyclic urea
Boc-Ala-OH
CO Me
CO2Me
CO2Me
O
2
HCl/MeOH
77%
HATU / DIEA
N +
N +
N +
N
NHBoc
N
NH2 .HCl
THF
78%
N
HN
Bu
Bu
Bu
NTf -
NTf2-
NTf2-
2
NHBoc
Boc-[MBHis][NTf ]-OMe 4a
2
H-[MBHis][NTf ]-OMe.HCl 6
2
Boc-Ala-[MBHis][NTf ]-OMe 8
2
HCl / H O
LiOH / H2O
quant.
2
quant.
O
H-Ala-Ot Bu
CO H
CO H
2
2
HATU / DIEA
NH CO tBu
2
N +
N +
N +
N
NH .HCl
N
NHBoc
THF
83%
N
NHBoc
2
Bu
Bu
Bu
NTf -
NTf -
NTf -
2
2
2
[
MBHis][NTf ].HCl 5
Boc-[MBHis][NTf ]-OH 7
Boc-[MBHis][NTf ]-Ala-OtBu 9
2
2
2
Scheme 2. Access to (S)-histidinium [MBHis][X] derivatives.

F. Guillen et al. / Tetrahedron Letters 47 (2006) 1245–1248
1247
drous methanol affording the aminoester hydrochloride
in 77% yield, or by saponification using lithium
hydroxide, quantitatively affording the N-protected
7. Tao, G.-H.; He, L.; Sun, N.; Kou, Y. Chem. Commun.
005, 3562–3564.
. Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591–
93.
2
6
8
9
5
aminoacid 7.
. Clavier, H.; Boulanger, L.; Audic, N.; Toupet, L.;
Mauduit, M.; Guillemin, J.-C. Chem. Commun. 2004,
In order to assess the ability of the novel imidazolium
aminoacid derivatives to undergo peptidic coupling at
either N- or C-terminal position, monoprotected amino-
acids 6 and 7 were reacted with N-Boc-alanine (respec-
tively, alanine tert-butylester) using HATU as the
coupling agent and DIEA as a base, affording the
1
224–1225.
1
0. Vallette, H.; Ferron, L.; Coquerel, G.; Gaumont, A.-C.;
Plaquevent, J.-C. Tetrahedron Lett. 2004, 45, 1617–
1619.
11. During the course of our work, Erker et al. described the
synthesis and ionic liquid properties of ‘symmetrical’ [Bz-
1
9
His(propyl)
R.; Erker, G. J. Organomet. Chem. 2005, 690, 5959–
972.
2. Miao, W.; Chan, T.-K. J. Org. Chem. 2005, 70, 3251–
255.
2
-OMe][Br]: Hannig, F.; Kehr, G.; Fr o¨ hlich,
desired dipeptide 8 (respectively, 9) in good yield
Scheme 2). Only one diastereoisomer of each dipeptide
(
5
was obtained, confirming that no racemization occurred
during the series of synthetic steps.
1
3
1
1
3. Jain, R.; Cohen, L. A. Tetrahedron 1996, 52, 5363.
4. Chivikas, C. J.; Hodges, J. C. J. Org. Chem. 1987, 52,
Worthy of note is that peptide coupling under standard
conditions leads to the desired targets in excellent yields
after purification, although starting from unprecedented
ionic structures.
3
591.
15. Solid histidine methyl ester dihydrochloride (1.21 g,
5 mmol) and carbonyldiimidazole (1.05 g, 6.5 mmol) were
heated to 80 ꢁC with vigorous mechanical stirring under a
flow of nitrogen. After 30 min, the viscous, slightly
yellowish liquid obtained was hydrolyzed with 5 mL
In this letter, we describe a handy access to a novel
family of chiral ionic liquids starting from an easily
available aminoacid, namely (S)-Histidine. The key
H
2
O, and the aqueous phase was extracted with
· 20 mL of CH Cl . The organic layer was dried over
anhydrous MgSO and concentrated under vacuum until
5
2
2
target [MBHis][NTf ] is obtained either unprotected,
2
4
mono N- or O-protected or fully protected on both
functions. Peptide coupling is shown to be as efficient
on this new aminoacid as in classical examples and
occurs without racemization. Further studies are cur-
rently underway to complete this new family of chiral
ionic liquids, to establish their structure/physicochemi-
cal data relationship, and to examine various organo-
catalyzed enantioselective reactions by means of these
new chiral tools.
precipitation of a white solid. Diethyl ether (200 mL) was
then added, and the product was filtered on a sintered
glass B u¨ chner, washed with ether and dried to give
analytically pure 1 as a white crystalline solid (802 mg,
82%).
16. Enantiomeric purity of 3 was ascertained by chiral HPLC
(
chiralcel AD-H, hexane/EtOH 1/1).
1
7. Analytical data for Boc-[MBHis][NTf ]-OMe 4a: mp
2
1
4
3
6.2 ꢁC; H NMR (CDCl , 400 MHz) d 0.97 (3H, t,
J = 7 Hz), 1.30–1.50 (2H, m), 1.41 (9H, s), 1.76–1.87 (2H,
m), 3.10 (1H, dd, J = 8 Hz, J = 16 Hz), 3.25 (1H, dd,
J = 5 Hz, J = 16 Hz), 3.80 (3H, s), 3.88 (3H, s), 4.0–4.2
Acknowledgements
(
2H, m), 4.51–4.56 (1H, m), 5.45–5.48 (1H, m), 7.10 (1H,
13
s), 8.67 (1H, s). C NMR (CDCl
3
, 75.5 MHz) d 13.4, 19.6,
The authors thank the R e´ seau Interr e´ gional de Recher-
che ‘Punch’Orga’ for financial support and a research
grant given to D. B., as well as Professor A.-C. Gau-
mont and Dr. J. Levillain for stimulating discussions.
26.5, 28.2, 32.0, 36.3, 47.3, 52.4, 53.2, 80.9, 119.9 (q,
1
19
J
CF = 321 Hz), 121.8, 131.5, 136.0, 155.7, 170.7.
F
2
0
NMR (CDCl
CHCl ). Anal. Calcd for C19
.87; N, 9.03; S, 10.33. Found: C, 36.86; H, 4.34; N, 8.98;
3
, 376.5 MHz) d ꢀ79.4. ½aꢁD +7.7 (c 1.2,
3
30 6 4 8 2
H F N O S
: C, 36.77; H,
4
+
S, 10.41. MS (ESI): m/z 340 (M , 32), 284 (100), 240 (4).
8. Although these salts present a melting point (determined
by DSC) above room temperature, ionic liquids are easily
found in supercooled state.
1
References and notes
1
. For recent reviews, see: Baudequin, C.; Baudoux, J.;
Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent,
J.-C. Tetrahedron: Asymmetry 2003, 14, 3081–3093; Ding,
J.; Armstrong, D. W. Chirality 2005, 17, 281–292;
Baudequin, C.; Br e´ geon, D.; Levillain, J.; Guillen, F.;
Plaquevent, J.-C.; Gaumont, A.-C. Tetrahedron: Asym-
metry 2005, 24, 3921–3945.
2
19. Synthesis of Boc-Ala-[MBHis][NTf ]-OMe 8: A round
bottomed flask was charged with 141 mg of 6 (0.25 mmol),
48 mg of Boc-(S)-Ala-OH (0.25 mmol, 1 equiv), and
97 mg of HATU (0.25 mmol, 1 equiv), and flushed with
argon. THF (10 mL) was then added and the mixture was
stirred at 0 ꢁC for 20 min. After addition of 70 lL of
DIEA (0.76 mmol, 3 equiv), the mixture was allowed to
warm up to room temperature. After 18 h, THF was
evaporated off and the residue was taken up in 10 mL of
2
3
4
5
. Baudoux, J.; Judeinstein, P.; Cahard, D.; Plaquevent, J.-C.
Tetrahedron Lett. 2005, 46, 1137–1140.
. Levillain, J.; Dubant, G.; Abrunhosa, I.; Gulea, M.;
Gaumont, A.-C. Chem. Commun. 2003, 2914–2915.
. Br e´ geon, D.; Levillain, J.; Guillen, F.; Plaquevent, J.-C.;
Gaumont, A.-C. ACS Symp. Ser., in press.
. (a) Wasserscheid, P.; B o¨ smann, A.; Bolm, C. Chem.
Commun. 2002, 200–201; (b) B o¨ smann, A.; Wasserscheid,
P.; Bolm, C.; Keim, W. DE10003708, 2001.
CH
2 · 8 mL of 10% aqueous citric acid solution, and 8 mL of
water. The organic layer was dried over MgSO . Concen-
tration under reduced pressure followed by chromatogra-
phy on silica gel (CH Cl /acetone: 8/2) led to pure 8 as a
2 2 3
Cl , washed with 8 mL of 1 M NaHCO solution,
4
2
2
2
D
0
colorless viscous oil (136 mg, 78%). ½aꢁ ꢀ15 (c 1.44,
1
3
acetone). H NMR (CD CN, 300 MHz) d 0.95 (3H, t,
6
. Fukumoto, K.; Yoshizawa, M.; Ohno, H. J. Am. Chem.
Soc. 2005, 127, 2398–2399.
J = 7.3 Hz), 1.22 (3H, d, J = 7.2 Hz), 1.30–1.45 (2H, m),
1.39 (9H, s), 1.70–1.85 (2H, m), 3.04 (1H, dd, J = 9.3 Hz,

1248
F. Guillen et al. / Tetrahedron Letters 47 (2006) 1245–1248
1
3
J = 16.2 Hz), 3.21 (1H, dd, J = 4.9 Hz, J = 16.2 Hz), 3.71
3H, s), 3.77 (3H, s), 3.94 (1H, m), 4.06 (2H, t, J = 7.5 Hz),
.65–4.75 (1H, m), 5.57 (1H, d, J = 4.9 Hz), 7.08 (1H, d,
282.4 MHz) d ꢀ80.66. C NMR (CD
3
CN, 75.5 MHz) d
(
4
13.6, 17.9, 20.0, 26.1, 28.4, 32.2, 36.8, 47.6, 51.1, 53.3, 55.9,
79.9, 120.8 (q, JC–F = 321 Hz), 122.7, 131.9, 136.3, 156.4,
171.4, 174.3.
1
9
3
J = 7.9 Hz), 7.18 (1H, s), 7.77 (1H, s). F NMR (CD CN,