Synthesis of a C3-symmetric furyl-cyclopeptide platform with anion recognition properties

Article abstract of DOI:10.1002/ejoc.201000219

A new furyl amino acid derivative was trimerized to give a linear peptide and finally was cyclized. The newly generated cyclopeptide was subjected to a conformational study in order to be considered as a C₃-symmetric platform for the ratio nal design of complex receptors. Moreover, the recognition properties towards cyanide, acetate and chloride anions were studied.

Full text of DOI:10.1002/ejoc.201000219

FULL PAPER
DOI: 10.1002/ejoc.201000219
Synthesis of a C3-Symmetric Furyl-Cyclopeptide Platform with Anion
Recognition Properties
Lidia Molina,[a] Elena Moreno-Clavijo,[a] Antonio J. Moreno-Vargas,*[a] Ana T. Carmona,[a]
and Inmaculada Robina*[a]
Keywords: Heterocycles / Cyclopeptides / Peptidomimetics / Anion receptors / Host-guest systems
A new furyl amino acid derivative was trimerized to give a
linear peptide and finally was cyclized. The newly generated
cyclopeptide was subjected to a conformational study in or-
der to be considered as a C3-symmetric platform for the ratio-
nal design of complex receptors. Moreover, the recognition
properties towards cyanide, acetate and chloride anions were
studied.
have been employed in the preparation of macrocyclic pep-
tides (Figure 1, a) that have been used as rigid molecular
platforms for the construction of receptors. Cyclopeptides
based on imidazole,[11] thiazole[12] and oxazole[12,13] have
been reported for this purpose, some of them were used
in the synthesis of larger receptors for the recognition of
phloroglucinol.[11a]
Introduction
The development of synthetic receptors with specific re-
cognition properties for anions is an important area in sup-
ramolecular chemistry that has attracted much attention
over the last years.[1] This interest is due to the important
role exerted by various anions in biological systems,[2] medi-
cine and catalysis,[3] industrial and environmental process-
es.[1a,4] In particular, cyanide anion devotes special attention
for its noxiousness that causes poisoning in biology and en-
vironment.[5] Nevertheless, its use in various industrial areas
is inevitable and is released into the environment as a toxic
contaminant.[6] Despite that a variety of synthetic receptors
for anions has been reported, the great importance of
cyanide ion has led to the development of an increasing
number of synthetic receptors for cyanide.[7] In general, the
binding interactions of anions with their receptors are weak
because anions are larger than isoelectronic cations, are pH-
dependent and, due to their diverse geometries, require a
higher degree of design for the receptors.[1a] The usually
weak nature of these interactions means that anion binding
relies on multiple interactions to achieve strength and selec-
tivity. It is known that amide groups with their intrinsic
ability to form hydrogen bonds, play an important role in
anion recognition, and especially amide-based macro-
cycles remain among the most popular designs for anion
hosts.[1a,1b,1j,8]
Heterocyclic amino acids are of interest because they are
substructures of biologically active marine cyclopeptides.[9]
They are also important as building blocks for peptidomi-
metics with the purpose of drug discovery.[10] Recently they
Figure 1. a) Heteroaromatic cyclopeptides as molecular platforms.
b) Furyl cyclopeptides as anion binding receptors. c) New furyl
cyclopeptide prepared.
Heteroaromatic cyclopeptides with restricted conforma-
tional degrees of freedom and multidentate H-bonding sites
are good candidates in the anion recognition field. How-
ever, despite the potential of this type of cyclopeptides, their
use as anion binding receptors has been scarce.[14] Furyl
cyclopeptides depicted in part b of Figure 1 were proven to
[a] Department of Organic Chemistry, Faculty of Chemistry,
University of Seville,
P. O. Box 1203, 41012 Seville, Spain
Fax: +34-954624960
E-mail: ajmoreno@us.es, robina@us.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000219.
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A. J. Moreno-Vargas, I. Robina et al.
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be moderate anion receptors for acetate and halides. These the azide function in 2 using H2S as reductive reagent. The
are the only examples of C3-symmetric furyl cyclopeptides solution phase peptide synthesis was carried out under
described in the literature.[14a,14b]
standard conditions (head to tail strategy) to give dimer 6
As part of our continuing interest in the synthesis and in 78% yield. Hydrogenolysis of the benzyl ester and subse-
applications of chiral furan amino acids,[10c,15] we present quent coupling with 4 gave linear tripeptide 7 in good over-
herein the synthesis of the new furyl-based cyclic peptide 1 all yield. Hydrogenolysis and acidic treatment of 7 followed
(Figure 1, c) from -xylose as inexpensive starting material by cyclization under high dilution conditions and final
and source of chirality. Cyclopeptide 1 decorated with a acetylation afforded furyl cyclopeptide 1 in 10% overall
number of precisely positioned binding units present obvi- yield (4 steps). Attempts to increase the yield of the cycliza-
ous advantages for the production of anion receptors. It tion step using FDPP and EDCI [1-ethyl-3-(3-dimethylami-
combines two interesting properties: it can be used as an nopropyl)carbodiimide] as coupling agents were unsuccess-
anion binding receptor due to the multidentate H-bonding ful. The lower yield in the cyclization step, comparing with
sites [–(CO)NH–, Ar–H] and also used as a molecular plat- other heteroaromatic-based cyclic peptide analogues[11–13]
form to generate C3-symmetric armed receptors by fixing (Figure 1, a), can be explained by the absence of internal
the ligands to its contained pendant functionalities hydrogen bonding interactions between the NH group and
(CH2OR). The conformational rigidity of the heteroarom- the oxygen of the furan ring in the intermediate unprotected
atic cyclopeptide and the chirality of the furyl amino acids acyclic peptide. These interactions could stabilize the ade-
used in its construction, will guarantee the orientation of quate conformation of the tripeptide before the cyclization.
the receptor arms. This compound represents the first mo-
lecular platform based on furan amino acids. The selective
recognition properties for cyclopeptide 1 towards different
anions (acetate, cyanide and chloride) have been investi-
1
gated by H NMR and MS.
Results and Discussion
In a previous paper, we reported a new methodology for
the stereoselective synthesis of α-furfurylamines from
sugars, that was applied to the synthesis of different furyl-
based amino acids.[15c,15d] Among them, amino acid 3 and
its azido ester precursor 2, were efficiently obtained from
-xylose and benzyl acetoacetate (Scheme 1).
Scheme 1. Stereoselective synthesis of furyl-based amino acids.
With furyl amino acid 3 in hand, the synthesis of furyl
cyclopeptide 1 was firstly attempted by one-pot cyclo-
trimerization under high dilution conditions (10–2–10–3 ),
based on reported procedures,[11–13] and using different cou-
pling reagents, PyBOP (benzotriazol-1-yl-oxytripyrrolidino-
phosphonium hexafluorophosphate) and FDPP (pentafluo-
rophenyl diphenylphosphinate). Unfortunately, compound
Scheme 2. Synthesis of furyl cyclopeptide 1.
1 was not detected.
We then decided to carry out the synthesis by cyclization
of the linear tripeptide precursor. Hydrogenation of azido
The NMR spectra of furyl cyclopeptide 1 in CD3CN and
1
derivative 2 and subsequent Boc protection followed by re- CDCl3, showed a perfect C3 symmetry. In the H NMR
action with PyBOP and DIPEA efficiently gave the hy- spectrum, the NH signal appeared at δ = 6.04 ppm with a
droxybenzotriazole-activated Boc-amino acid 4 that was coupling constant 3JNH,CH of 9.6 Hz in CDCl3. This chemi-
stable and could be purified by column chromatography cal shift is lower than other δ values for NH signals
(Scheme 2).[16] Amino ester 5 was obtained by reduction of (Ͼ6.7 ppm) of heteroaryl cyclopeptides where a network of
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Cyclopeptide with Anion Recognition Properties
intramolecular NHǞX (ring, X = N in Figure 1, a and X structure, as key pendant functionalities in the design of a
= O in Figure 1, b) H-bonds is possible.[11–13,14b] Moreover, possible receptor, is ca. 7.2 Å. In the internal cavity of the
a strong NOE between H-4 and the –NH– group was also cyclopeptide the distance between –NH– is ca. 4.6 Å. These
observed. All these facts are in agreement with the pro- parameters are very important in order to use this molecule
posed structure for compound 1, where the oxygen atom is as a platform for the rational design of complex receptors.
outside of the internal cavity. A structural analysis of com-
The ability of compound 1 to complex cyanide, acetate
1
pound 1 by molecular modeling using MacroModel[17] and and chloride anions was determined by H NMR titrations
the MM2* force field[18] was performed. The energy-mini- (see Supporting Information) in CD3CN following the pro-
mized structure thus obtained showed H–N–Cα–H dihedral cedure described by Kelly and co-workers.[20] The addition
angles of the three amide linkages of 169° which are sup- of anions (guest) in the form of tetrabutylammonium
3
ported by a JNH,CH of 9.6 Hz.
(TBA) salts to the solution of cyclopeptide 1 (host) caused
The analysis showed that the furan moieties do not form significant downfield shifts of the amide NH and internal
1
a single plane but have a “bowl-like” structure[19] with three aromatic H-4 signals in the H NMR spectra (see Figure 3
pendant functionalities (CH2OAc, Figure 2). The average for cyanide), suggesting the formation of very tightly bound
distance between the three oxygens of the acetoxy groups H-bonded complexes by anion nested inside the macro-
(oxygens linked to methylene groups) in the minimized cyclic cavity. The initial chemical shifts of NH and H-4 pro-
tons of the host were 6.65 and 6.60 ppm, respectively. After
addition of an excess of tetrabutylammonium cyanide
(TBACN) ([G]/[H] = 14), the NH shifted to 8.33 ppm
(∆δmax = 1.68 ppm); the H-4 shift was smaller (∆δmax
=
1.07 ppm). With tetrabutylammonium acetate (TBAA) at
the saturation point ([G]/[H] = 6), the NH amide and H-4
aromatic proton shifts (∆δmax
) were 1.92 ppm and
1.08 ppm, respectively. In the case of tetrabutylammonium
chloride (TBACl), the amide and aromatic proton shifts
(∆δmax) were 1.04 ppm and 1.23 ppm, respectively, at the
saturation point ([G]/[H] = 4.5). Typical titration curves are
shown in Figure 4 (bottom). The stoichiometry of complex-
ation of 1 with the corresponding TBA salt of the anion
was determined using Job’s method (Figure 4, top). The
representation showed a maximum at ca. 0.5 mol fraction
(XH) in all the cases, confirming the formation of 1:1 com-
plexes. These complexes could be detected by mass spec-
trometry (ESI). The molecular ions [M]– of the complexes
1·AcO– (m/z 686.2) and 1·Cl– (m/z 662.2) and [M – H]– of
the complex 1·CN– (m/z 652.2), are observed together with
Figure 2. Structural analysis of cyclopeptide 1 by molecular model-
ing using MacroModel and the MM2* force field.
1
Figure 3. Plots of H NMR (500 MHz) spectra of 1 on addition of TBACN using CD3CN as solvent.
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A. J. Moreno-Vargas, I. Robina et al.
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Figure 4. Job plots (top) and 1H NMR titration plots (bottom) for the complexation of cyclopeptide 1 with tetrabutylammonium acetate,
cyanide and chloride salts in CD3CN solution.
Figure 5. ESI spectra for the complexation of 1 with cyanide.
the corresponding fragmentation through consecutive loss
of AcOH and CNH in the two first cases (see Figure 5 for 1.6ϫ104 –1, which is in agreement with the geometry of
cyanide complexation). the central cavity of 1. It is worth noting the evidence that
The best result was obtained with spheric chloride, Ka =
The association constants (Ka) were calculated as aromatic C–H groups within the anionophore cavity par-
averaged values obtained from non-linear fitting of a 1:1 ticipate in bonding[22] and lead to enhanced anion-binding
binding model[21] to the graphic that represents the H-4 aro- affinity. The presence of an electron-withdrawing group, as
matic shift towards anion concentration. While Ka calcu- the amide group, on the furan ring (Figure 6) strengthens
lated for trigonal acetate was 1.0ϫ103 –1, binding with this anion hydrogen bond as was recently reported by
cylinder cyanide was slightly higher, Ka = 1.6ϫ103 –1.
others for phenyl rings.[23]
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Cyclopeptide with Anion Recognition Properties
solution was concentrated to dryness and purified by column
chromatography (dichloromethane/methanol, 10:1) to give
(600 mg, 96%) as a colourless oil. [α]2D3 = +13 (c = 1.38, CH2Cl2);
= 3359 (OH), 2922, 1712 (CO), 1422, 1226, 1071; 1H NMR
5
ν
˜
max
(300 MHz, CD3OD, 25 °C): δ = 2.54 (s, 3 H, CH3), 3.66 (dd, J2Јb,1Ј
= 6.9 Hz, 1 H, 2Јb-H), 3.77 (dd, J2Јa,2Јb = 10.9, J2Јa,1Ј = 5.2 Hz, 1
H, 2Јa-H), 3.95 (m, 1 H, 1Ј-H), 5.26 (s, 2 H, CH2Ph), 6.55 (s, 1-H,
4-H), 7.40–7.32 (m, 5 H, Ar-H) ppm. 13C NMR (75.4 MHz,
CD3OD, 25 °C): δ = 165.2 (COOBn), 160.2 (C-2), 154.8 (C-5),
137.8, 129.6, 129.2, 129.2 (6 C, C-aromat.), 115.0 (C-3), 108.0 (C-
4), 67.0 (CH2Ph), 65.7 (C-2Ј), 52.3 (C-1Ј), 13.8 (CH3) ppm. m/z
(CI) 274.1075 [(M – H)+. C15H16O4N requires 274.1079], 259 [(M –
NH2)+, 46%].
Figure 6. Aryl CH-anion hydrogen bonds in complexation of
anions.
Benzyl
ethyl]-2-methyl-3-furamide]-1-deoxy-2-hydroxyethyl}-2-methylfuran-
3-carboxylate (6): To solution of compound (290 mg,
5-{(R)-1-[5-[(R)-1-(tert-Butoxycarbonylamino)-2-hydroxy-
a
4
Conclusions
0.72 mmol) in DMF (10 mL), a solution of 5 (198 mg, 0.72 mmol)
in DMF (10 mL) and DIPEA (504 µL, 2.88 mmol) was added. The
reaction mixture was stirred for 3 h. Then, the solution was evapo-
rated to dryness and the resulting crude was purified by column
In summary, we have synthesized the first molecular plat-
form derived from furan. This C3-symmetric furyl cyclopep-
tide has shown good recognition properties towards cya-
nide, acetate and chloride anions. This ability has been en-
hanced due to the formation of an unusual hydrogen bond
between the furyl CH and the guest anion.
chromatography (dichloromethane/methanol, 25:1) to give
(300 mg, 77%) as a colourless oil. [α]2D3 = +67 (c = 0.46 in CH2Cl2);
= 3348 (OH), 2922, 1713 (CO), 1520, 1366, 1228, 1166, 1070,
6
ν
˜
max
1
776; H NMR (300 MHz, CD3OD, 25 °C): δ = 1.44 [s, 9 H, (CH3)
3C], 2.51 [s, 3 H, CH3(A)], 2.53 [s, 3 H, CH3(B)], 3.72 [dd, J2ЈbB,1ЈB
= 6.5 Hz, 1 H, 2Јb-H(B)], 3.78 [dd, J2ЈaB,2ЈbB = 11.3, J2ЈaB,1ЈB
=
5.9 Hz, 1 H, 2Јa-H(B)], 3.84 [dd, J2ЈbA,1ЈA = 6.5 Hz, 1 H, 2Јb-H(A)],
3.89 [dd, J2ЈaA,2ЈbA = 11.3, J2ЈaA,1ЈA = 5.9 Hz, 1 H, 2Јa-H(A)], 4.68
[m, 1 H, 1Ј-H(A)], 5.19 [m, 1 H, 1Ј-H(B)], 5.26 (s, 2 H, CH2Ph),
6.55 [s,1 H, 4-H(B)], 6.60 [s, 1 H, 4-H(A)], 7.42–7.31 (m, 5 H, Ar-
H) ppm. 13C NMR (125.7 MHz, CD3OD, 25 °C): δ = 166.1
(CONH), 165.2 (COOBn), 160.3 (CO of Boc), 157.8 [2 C, C-
2(A,B)], 152.7 [2 C, C-5(A, B)], 137.7, 129.6, 129.2, 129.2 (6 C, C-
aromat.), 117.2 (C-3A), 115.0 (C-3B), 108.7 (C-4B), 106.9 (C-4A),
80.6 [(CH3)3C], 67.0 (CH2Ph), 63.8 (C-2ЈA), 63.5 (C-2ЈB), 52.1 (C-
1ЈA), 50.4 (C-1ЈB), 28.7 [(CH3)3C], 13.8 (CH3A), 13.6 (CH3B) ppm.
Experimental Section
Benzotriazol-1-yl 5-[(R)-1-N-(tert-Butoxycarbonyl)amino-2-hydro-
xyethyl]-2-methylfuran-3-carboxylate (4): A solution of 2 (331 mg,
1.1 mmol) in MeOH (20 mL) was hydrogenated under atmospheric
pressure for 3 h, using Pd/C (10%) as catalyst. Then, the solution
was filtered through celite and the catalyst washed with MeOH.
The filtered solution was concentrated in vacuo to give crude
amino acid 3. The resulting crude was dissolved in EtOH (8 mL)
and (Boc)2O (368 mg, 1.65 mmol) followed by Et3N (233 µL,
1.65 mmol) were added to the solution. The reaction mixture was
stirred for 1 h. Then, the solvent was evaporated, the resulting
crude was dissolved in DMF (8 mL) and PyBOP (435 mg,
0.81 mmol) and DIPEA (283 µL, 1.65 mmol) were added. The re-
action mixture was stirred for 1 h, then the solvent was evaporated,
the resulting crude was dissolved in AcOEt and washed with satu-
rated aqueous solution of NaHCO3 and brine. The organic phase
was dried (Na2SO4), filtered and the solvents were evaporated. The
resulting crude was purified by column chromatography (AcOEt/
petroleum ether, 1:1) to give 4 (218 mg, 50%) as a colourless oil.
m/z (FAB) 565.2151 [[M
565.2162].
+
Na]+. C28H34N2O9Na requires
Benzyl 5-{(R)-1Ј-[5-(R)-1Ј-(tert-Butoxycarbonylamino)-2Ј-hydroxy-
ethyl]-2-methyl-3-furamide-(NǞ1Ј)-5-[(R)-2Ј-hydroxyethyl]-2-
methyl-3-furamide-(NǞ1Ј)-2Ј-hydroxyethyl}-2-methylfuran-3-
carboxylate (7): A solution of 6 (307 mg, 0.55 mmol) in EtOH
(35 mL) was hydrogenated under atmospheric pressure for 2 h,
using Pd/C (10%) as catalyst. Then, the solution was filtered
through celite and the catalyst washed with EtOH. The filtered
solution was concentrated in vacuo. The resulting residue was dis-
solved in DMF (15 mL) and a solution of 5 (151 mg, 0.55 mmol)
in DMF (20 mL), DIPEA (385 µL, 2.2 mmol) and PyBOP (322 mg,
0.61 mmol) were added. The reaction mixture was stirred for 3 h,
then the solution was evaporated and purified by column
chromatography (diethyl ether/acetone, 3:1) to give 7 (376 mg,
[α]2D3 = +39 (c = 1.36 in CH Cl ); ν
= 3397 (OH), 2961, 1793
˜
max
2
2
(CO), 1713 (CO), 1368, 1166, 960, 743; 1H NMR (300 MHz,
CD3OD, 25 °C): δ = 1.47 [s, 9 H, (CH3)3C], 2.67 (s, 3 H, CH3),
3.80 (dd, 1 H, 2Јb-H), 3.85 (dd, J2Јa,2Јb = 11.2 Hz, 1 H, 2Јa-H), 4.79
(t, J1Ј,2Јa = J1Ј,2Јb = 6.0 Hz, 1 H, 1Ј-H), 6.83 (s, 1 H, 4-H), 7.52 (m,
1 H, Ar-H), 7.66–7.64 (m, 2 H, Ar-H), 8.06 (br. dt, J = 8.6, J =
0.8 Hz, 1 H, Ar-H) ppm. 13C NMR (754 MHz, CD3OD, 25 °C): δ
= 164.7 (COOBt), 161.0 (CO of Boc), 155.1 (C-2), 144.5 (C-5),
130.3, 126.5, 120.8, 109.9 (6 C, C-aromat.), 109.6 (C-3), 107.7 (C-
4), 80.7 [(CH3)3C], 63.7 (C-2Ј), 52.0 (C-1Ј), 28.7 [(CH3)3C], 14.1
(CH3)ppm. MS (CI): m/z = 403.1628 [[M + H]+. C19H23O6N4 re-
quires 403.1618], 268 [(M – OBt)+, 26%] .
96%) as a white solid. [α]2D4 = +41 (c = 0.73 in CH Cl ); ν
=
˜
max
2
2
3332 (OH), 2928, 1697 (CO), 1642 (CO), 1581, 1523, 1367, 1229,
1166, 1070, 737; 1H NMR (500 MHz, CD3OD, 25 °C): δ = 1.41 [s,
9 H, (CH3)3C]; 2.51 [s, 6 H, CH3(A, B)], 2.53 [s, 3 H, CH3(C)], 3.73
[dd, J2ЈbA,1ЈA = 6.3 Hz, 1 H, 2Јb-H(A)]; 3.78 [dd, J2ЈaA,2ЈbA = 11.2,
J2ЈaA,1ЈA = 5.9 Hz, 1 H, 2Јa-H(A)], 3.92–3.82 [m, 4 H, 2Јa-H(B, C),
2Јb-H(B, C)], 4.68 [m, 1 H, 1Ј-H(A)], 5.18 [t, J1ЈA,2ЈA = J1ЈB,2ЈB
=
Benzyl 5-[(R)-1-Amino-2-hydroxyethyl]-2-methylfuran-3-carboxylate 6.0 Hz, 2 H, 1Ј-H(B, C)], 5.25 (s, 2 H, CH2Ph), 6.54 [s, 1 H, 4-
(5): SH2 was bubbled for 1 h through a solution of 2 (685 mg,
2.28 mmol) in pyridine/H2O, 1:1 (40 mL), then the mixture was
stirred overnight. The solvent was evaporated, the resulting crude
was dissolved in MeOH and filtered through celite. The filtered
H(A)], 6.60 [s, 1 H, 4-H(B)], 6.65 [s, 1 H, 4-H(C)], 7.41–7.31 (m, 5
H, Ar-H) ppm. 13C NMR (125.7 MHz, CD3OD, 25 °C): δ = 166.1
[2 C, CONH(A, B)], 165.2 (COOBn), 160.3 (CO of Boc), 157.9 (C-
2C), 157.8 [2 C, C-2(A, B)], 152.7 [2 C, C-5(B, C)], 152.2 (C-5A),
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A. J. Moreno-Vargas, I. Robina et al.
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137.7, 129.6, 129.2 (6 C, C-aromat.), 117.2 [2 C, C-3(A, B)], 115.3
(C-3C), 108.7 (C-4C), 107.2 (C-4B), 106.9 (C-4A), 80.6 [(CH3)3C],
67.0 (CH2Ph), 63.9 (C-2ЈA), 63.5 [2 C, C-2Ј(B,C)], 52.1 (C-1ЈA),
50.6, 50.4 [C-1Ј(B,C)], 28.7 [(CH3)3C], 13.8 (CH3C), 13.6 [2 C,
CH3(A,B)] ppm. m/z (FAB) 732.2736 [[M + Na]+. C36H43O12N3Na
requires 732.2744].
where
δ is the chemical shift for NH or H-4 at each titration point, δh is
the initial chemical shift for NH or H-4 (host only), δc is the chemi-
cal shift for NH or H-4 when the receptor is entirely bound, [Ho]/
[Go] is [host]/[guest] at each titration point (guest and host concen-
trations for each point take into account the changes in volume).
Furyl Cyclopeptide 1: A solution of 7 (90 mg, 0.125 mmol) in EtOH
(8 mL) was hydrogenated ander atmospheric pressure for 2 h, using
Pd/C (10%) as catalyst. Then the solution was filtered through ce-
lite and the catalyst washed with EtOH. The filtered solution was
concentrated in vacuo. The resulting residue was dissolved in a
solution of TFA (20%) in CH2Cl2 and the mixture was stirred for
20 min. Then the solution was evaporated to dryness, the resulting
crude was dissolved in DMF (250 mL), PyBOP (100 mg,
0.19 mmol) and DIPEA (218 µL, 1.25 mmol) were added and the
mixture was stirred for 19 d. Then, the mixture was evaporated to
dryness and the resulting crude was acetylated (1 mL Ac2O/1 mL
pyridine) overnight. Then the solvent was evaporated, the residue
was dissolved in dichloromethane and washed with HCl (1 ), satu-
rated aqueous solution of NaHCO3 and brine. The organic phase
was dried (Na2SO4), filtered, and purified by column chromatog-
raphy (diethyl ether/acetone, 6:1) to give 1 (8 mg, 10%) as a colour-
less oil; 1H NMR (500 MHz, CDCl3, 25 °C): δ = 2.10 (s, 9 H,
CH3CO), 2.51 (s, 9 H, CH3), 3.37 (dd, J2Јb,1Ј = 4.3 Hz, 3 H, 2Јb-
H), 4.50 (dd, J2Јa,2Јb = 11.5, J2Јa,1Ј = 6.2 Hz, 3 H, 2Јa-H), 5.47–5.41
(m, 3 H, 1Ј-H), 6.04 (d, JNH,1Ј = 9.6 Hz, 3 H, NH), 6.33 (s, 3 H,
4-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 171.2 (3 C,
CH3CO), 163.5 (3 C, CONH), 157.5 (3 C, C-2), 151.8 (3 C, C-5),
116.8 (3 C, C-3), 106.3 (3 C, C-4), 64.7 (3 C, C-2Ј), 47.7 (3 C, C-
1Ј), 21.0 (3 C, CH3CO), 13.3 (3 C, CH3) ppm. m/z (FAB) 650.1952
[[M + Na]+. C30H33O12N3Na requires 650.1962].
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for all new compounds,
NMR plots for titration experiments and mass spectra for cyclo-
peptide–anion complexes.
Acknowledgments
We thank the Spanish Ministerio de Educación y Ciencia (MEC)
(CTQ2008-01565/BQU) and the Junta de Andalucía (FQM-345)
for financial support. E. M. C. thanks the MEC for an FPU fellow-
ship. We also thank CITIUS of the University of Seville for NMR
and MS facilities, and P. Carmona for helpful discussion on associ-
ation constant determination.
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General Procedure for NMR Titrations: The titration of cyclic furyl-
carbopeptoid receptor 1 with acetate, cyanide and chloride was car-
ried out following the procedure described by Kelly and co-
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(3.4 mg, 0.5 mL) in a NMR tube. A 0.038  solution of tetra-
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Published Online: June 9, 2010
Eur. J. Org. Chem. 2010, 4049–4055
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4055