Synthesis, structures, and properties of nine-, twelve-, and eighteen-membered N-benzyloxyethyl cyclic α-peptoids

Article abstract of DOI:10.1039/b806508j

N-Benzyloxyethyl cyclic α-peptoids of various size were prepared and their conformational features were investigated by means of computational, spectroscopic, and X-ray crystallographic studies. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806508j

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Synthesis, structures, and properties of nine-, twelve-, and eighteen-
membered N-benzyloxyethyl cyclic a-peptoidsw
N. Maulucci,a I. Izzo,*a G. Bifulco,b A. Aliberti,a C. De Cola,a D. Comegna,a
C. Gaeta,a A. Napolitano,b C. Pizza,b C. Tedesco,a D. Flotc and F. De Riccardis*a
Received (in Cambridge, UK) 16th April 2008, Accepted 16th May 2008
First published as an Advance Article on the web 3rd July 2008
DOI: 10.1039/b806508j
N-Benzyloxyethyl cyclic a-peptoids of various size were prepared
and their conformational features were investigated by means of
computational, spectroscopic, and X-ray crystallographic studies.
Peptoids, an archetypal example of bioinspired peptidomimetics,
show unique structural and physical properties.1 The conforma-
tional ordering of their achiral polyimide backbone is dictated by
stereoelectronic effects caused by N- (and C-) substitution2 and/or
by cyclization.3–6 In particular, the prediction and the assessment
Fig. 1 Predicted lowest energy conformations for compounds 1, 2
and 3 (atom type: C gray, N blue, O red); hydrogen atoms and phenyl
of the covalent constraints induced by macrolactamization ap-
groups omitted for clarity.
pears crucial for the design of conformationally restricted peptoid
templates as preorganized synthetic scaffolds or receptors.
mechanical (QM) refinement of the geometries and energies (see
In this communication, we report the synthesis and the
ESIw for details), predicted, for the highly strained cyclo-a-tripep-
conformational features of cyclic tri-, tetra-, and hexa-N-
toid 1, a C3-symmetric ‘‘crown’’7 conformation (previously found
benzyloxyethyl glycines (1–3). The structural studies were
for the all-cis N,N0,N00-triallyl-cyclo-triglycine)4 and, for the 12-
based on computational, spectroscopic, and X-ray crystal-
membered 2, a center of symmetry (i) due to a cis-trans-cis-trans
(ctct) ‘‘chair’’8 arrangement. The prediction of an all-trans amide
lographic investigations. We will also discuss the complexing
properties displayed by the cyclohexapeptoid 3.
geometry for 3 was tentative, due to the multitudinous, energeti-
cally equivalent, possible backbone orderings.
The synthesis of the linear N-benzyloxyethyl glycine oligomers
was accomplished both in solution (Scheme 1) and through a
The studies on the cyclic peptoids (1–3) started with a pre-
liminary lowest energy conformational search (Fig. 1). Molecular
mechanics and dynamics calculations, followed by quantum
a Department of Chemistry, University of Salerno, Via Ponte Don
Melillo, I-84084 Fisciano Salerno, Italy. E-mail: dericca@unisa.it.
E-mail: iizzo@unisa.it; Fax: +39 089 969603; Tel: +39 089
969552
Scheme 1 Synthesis of 1–3. Reagents and conditions: (a) BnOCH2-
CHO (5), Et3N, NaBH(OAc)3, CH2Cl2, 69%; (b) i. LiOH, diox-
ane–H2O (1 : 1), ii. NaHCO3, Boc2O quant.; (c) 6, BOP-Cl, Et3N,
CH2Cl2, 67%; (d) LiOH, THF, 92%; (e) HCl (4 M in 1,4-dioxane),
AcOEt (1 : 1), quant.; (f) BOP-Cl, Et3N, CH2Cl2, 58%; (g) i. LiOH,
THF–H2O (1 : 1) 76%, ii. HCl (4 M in 1,4-dioxane), AcOEt (1 : 1),
quant.; (h) BOP-Cl, Et3N, CH2Cl2, 63%; (i) LiOH, THF–H2O (1 : 1)
65%; (j) HCl (4 M in 1,4-dioxane), AcOEt (1 : 1), quant.; (k) CIP,
DIPEA, CH3CN, 48 h, 54%; (l) i. LiOH, THF–H2O (1 : 1) 80%, ii.
HCl (4 M in 1,4-dioxane), AcOEt (1 : 1), quant.
b Department of Pharmaceutical Sciences, University of Salerno, Via
Ponte Don Melillo, I-84084 Fisciano Salerno, Italy
c EMBL, 6 rue J. Horowitz, BP 181, F-38042 Grenoble CEDEX 9,
France
w Electronic supplementary information (ESI) available: Experimental
section with a list of abbreviations. CCDC reference numbers 685414
and 685415. For ESI and crystallographic data in CIF or other
electronic format, see DOI: 10.1039/b806508j
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solid-phase approach (‘‘monomer’’ approach). The key carboxy-
and N-protected N-alkylated glycines (6 and 7, respectively) were
easily obtained through reductive amination9 and straightforward
protecting group processing. Successive couplings and chemose-
lective deprotections yielded the required oligomers 12, 15 and 17.
Alternatively, HATU or PyBOP-induced oligomerization of
N-fluorenylmethoxycarbonyl-N0-benzyloxyethyl glycine on 2-
chlorotrityl resin (average coupling yield: 97%), gave the
oligomers 12, 15 and 17 with considerable purity (RP-HPLC
and ESI-MS analysis) and in shorter times.
Head-to-tail macrocyclizations of the linear N-substituted gly-
cines were attempted using a variety of condensing agents and
high dilution conditions (2.0 ꢁ 10ꢂ3 M). The best results were
achieved in the presence of PyBOP, FDPP or HATU in DMF.
The HATU-mediated cyclization of the linear 12 gave the
highly strained N,N0,N00-tribenzyloxyethyl-cyclo-triglycine 1 in
15% yield.10 The spectroscopic data (1H- and 13C-NMR) con-
firmed the predicted C3-symmetric all-cis ‘‘crown’’ conformation
(Fig. 1).4 The GIAO11 calculated 1H-NMR chemical shifts, were
in agreement with the experimental values (e.g. diastereotopic
intra-annular glycine proton doublets: Ddtheor. 0.74 ppm, Ddexp.
0.72 ppm, CDCl3 solution, 400 MHz, see ESIw). Variable-tem-
Fig. 3 1H NMR spectra of free 3 (a) (CD3CN–CDCl3 9 : 1 solution,
25 1C, [3] = 4.0 mM, 400 MHz) and in the presence of 0.5 eq. (b) or 1.5
eq. (c) of sodium picrate. Residual solvent peaks are labelled with
.
auspice for the complexation studies. In fact, the stepwise addition
of sodium picrate to 3, induced the formation of a new chemical
species, whose concentration increased with the gradual addition
of the guest (Fig. 3b and c). The conformational equilibrium
between the free host and the sodium complex, resulted in being
slower than the NMR time scale, giving, with an excess of guest, a
1
remarkably simplified H NMR spectrum, reflecting the forma-
1
perature (VT) H-NMR experiments demonstrated, for the gly-
tion of a 6-fold symmetric species (Fig. 3c).
cine protons, a coalescence temperature at 405 K (C2D2Cl4
solution, 300 MHz, DGz = 19.0 ꢃ 0.5 kcal molꢂ1 12).
A conformational search on 3 as a sodium complex sug-
gested the presence of an S6-symmetry axis passing through
the intracavity sodium cation (Fig. 4). The electrostatic
(ion–dipole) forces stabilize this conformation, hampering
the ring inversion up to 425 K.
Differently from the 9-membered cyclopeptoid 1, cyclization of
the N-substituted tetraglycine 15 proved easy to accomplish,
giving 2 in 65% yield, using PyBOP or FDPP as the condensing
agent. The presence of a centre of symmetry (Fig. 1) was inferred
The conformation of the corand 3 is influenced also by
dipole–dipole interactions. In fact, gradual addition of an excess
of the hydrogen bond donors ammonium and benzylammonium
picrates to a 9 : 1 CD3CN–CDCl3 solution of the free host, froze 3
in a 6-fold symmetric species (1H NMR, 400 MHz, Fig. 5a and b).
A QM refined conformational search demonstrated, for the
hydrogen-bonded complexes, the structures reported in Fig. 6.
The association constants (Ka) for the complexation of 3 to
the first group alkali metals and ammonium, were evaluated in
H2O–CHCl3 following Cram’s method (Table 1).15 The results
presented in Table 1 show a good degree of selectivity for the
smaller cations, with a peak for Na+.
1
by the appearance, in the H- and 13C NMR spectra, of two
independent resonance peak patterns. Theoretical prediction of
the 1H NMR values, performed at the QM level (see ESIw),
showed full agreement with the recorded spectral data [e.g.
diastereotopic intra-annular proton doublets: Ddtheor.: (a) 2.34
ppm, (b) 0.12 ppm; Ddexp.: (a) 1.94 ppm, (b) 0.08 ppm, respec-
tively; C2D2Cl4 solution, 300 MHz, see ESIw]. VT 1H-NMR
studies indicated no hint of coalescence up to 425 K (C2D2Cl4
solution, 300 MHz) for the intra-annular protons doublets.
Finally, a single crystal X-ray analysisz (Fig. 2), demonstrated a
ctct ‘‘chair’’ tetralactam core geometry in agreement with the
theoretical prediction (Fig. 1).13
We attempted crystallization of the first group alkali metal
picrate salt adducts. After unsuccessful results, we obtained
needle like crystals, suitable for X-ray structure analysis, of 3
as a 2 : 3 complex with strontium picrate.z The structure
obtained, the first to be solved for a metal complex of a cyclic
The synthesis of 3 proceeded smoothly both in the presence of
PyBOP or FDPP (497% yield, RP-HPLC analysis, see ESIw).
The complexity of the rt H NMR spectrum recorded for the
1
cyclic 3 invoked the contemporary presence of more than one
conformer in slow exchange on the NMR time scale (Fig. 3a).14
The conformational disorder in solution was seen as a propitious
Fig. 4 Picture of the predicted lowest energy conformation for the
complex 3 with sodium. The peptoid bonds display an all-trans
geometry (atom type: C gray, N blue, O red, Na magenta). Hydrogen
atoms have been omitted for clarity.
Fig. 2 X-Ray crystal structure of 2 reflecting the ctct stereochemical
arrangement (atom type: C gray, N blue, O red). Hydrogen atoms
have been omitted for clarity.
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The macrolactam core of the solid state construct is in
excellent agreement with the theoretical studies, consolidating
the supposed S6-symmetry of the host in the sodium, ammo-
nium and benzylammonium complexes.
Financial support from the University of Salerno. We thank
Prof. P. Neri (University of Salerno) for valuable discussion
and ESRF for beamtime at ID23-2.
Fig. 5 1H NMR spectra of 3 (CD3CN–CDCl3 9 : 1 solution, 25 1C,
[3] = 4 mM, 400 MHz) in the presence of 4.0 eq. of (a) ammonium and
+
+
(b) benzylammonium picrate ( NH4 (a), and PhCH2NH3 (b)
protons). Residual solvent peaks are labelled with
Notes and references
.
z Crystal data for 2. Formula: C44H52N4O8, FW = 764.90, mono-
clinic, space group C2/c(no. 15), Z = 4, a = 18.554(3), b = 5.387(2),
c = 40.021(5) A, b = 98.171(5)1, V = 3959.5(17) A3, Dx = 1.283 g
cmꢂ3, mcalc = 0.089 mmꢂ1
.
Crystal data for 32ꢄ[Sr(Picr)2]3. Formula: C168H168N30O66Sr3ꢄ2H2O,
FW = 3958.20, monoclinic, space group P21/n, Z = 2, a = 18.895(5),
b = 24.546(3), c = 9.252(3) A, b = 96.304(11)1, V = 8875(3) A3, Dx
= 1.481 g cmꢂ3, mcalc = 0.355 mmꢂ1
.
1 R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D. Huebner, D.
A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg, C. K.
Marlowe, D. C. Spellmeyer, R. Tan, A. D. Frankel, D. V. Santi,
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W. H. Moos, J. Am. Chem. Soc., 1992, 114, 10646.
2 J. A. Patch, K. Kirshenbaum, S. L. Seurynck, R. N. Zuckermann
and A. Barron, in Pseudo-peptides in Drug Development, ed. P. E.
Nielsen, Wiley-VCH, Weinheim, 2004, pp. 1–35.
Fig. 6 Predicted lowest energy conformations for the complex be-
tween 3 and: (a) ammonium and (b) benzylammonium picrate (atom
type: C gray, N dark blue, O red, polar H sky blue). The non-polar
hydrogen atoms have been omitted for clarity.
3 S. B. Y. Shin, B. Yoo, L. J. Todaro and K. Kirshenbaum, J. Am.
Chem. Soc., 2007, 129, 3218.
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5 O. Roy, S. Faure, V. Thery, C. Didierjean and C. Taillefumier,
Org. Lett., 2008, 10, 921.
Table 1 R, Ka, and DG1 for cyclopeptoid host 3 complexing picrate
salt guests in CHCl3 at 25 1C; figures within ꢃ10% in multiple
experiments, guest : host stoichiometry for extractions was assumed
as 1 : 1
6 L. A. Wessjohann, C. K. Z. Andrade, O. E. Vercillo and D. G.
Rivera, in Targets in Heterocyclic Systems, ed. O. A. Attanasi and
D. Spinelli, Italian Society of Chemistry, Rome, 2007, vol. 10,
pp. 24–53.
7 Molecular mechanics calculations (AMBER force field, see ESIw)
demonstrated that the unsymmetric ‘‘boat’’ conformer
(cis-cis-trans) was 98 kJ molꢂ1 less stable than the all-cis.
8 The ccct and the cccc cyclotetrapeptoid conformations, calculated
at the DFT MPW1PW91/6-31G level (see ESIw) were, respectively,
13 and 35 kJ molꢂ1 less stable than the ctct. For an interesting
review on the conformational states of cyclotetrapeptides, see: N.
ꢂDG1/
ꢂ1
Picrate salt
Ra
Ka/10ꢂ3
M
kcal molꢂ1
Li+
Na+
K+
0.17
0.35
0.24
0.126
0.085
0.18
950
3300
940
410
210
380
8.1
8.9
8.1
7.7
7.2
7.6
Rb+
Cs+
+
NH4
a
[Guest]/[host] in CHCl3 layer at equilibrium.
Loiseau, J.-M. Gomis, J. Santolini, M. Delaforge and F. Andre
´
,
Biopolymers, 2003, 69, 363.
9 A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Marynoff
and R. D. Shah, J. Org. Chem., 1996, 61, 3849.
10 The strained nine-membered cyclopeptoid 1 was accompanied by a
complex mixture of higher order oligo- and cyclooligomers (RP-
HPLC and MS-analysis). PyBOP, FDPP, PyBrOP, and DPPA
condensing agents gave, invariably, lower yields (see ESIw).
11 R. Ditchfield, J. Chem. Phys., 1972, 56, 5688; K. Wolinski, J. F.
Hinton and P. Pulay, J. Am. Chem. Soc., 1990, 112, 8251.
12 R. J. Kurland, M. B. Rubin and W. B. Wise, J. Chem. Phys., 1964,
40, 2426.
13 No group 1 metal cations and ammonium picrate extraction was
observed for 1 and 2 using standard two-phase experiments
(see ESIw). Procedure: C. J. Pedersen, Fed. Proc., 1968, 27, 1305.
14 The resonance of more than the expected signals in the rt 13C
NMR spectrum of 3 suggested the contemporary presence of two
or more slowly equilibrating conformations. Simplification of the
NMR spectra into a set of broad singlets was observed at T = 415
K (C2D2Cl4 solution, 300 MHz). See ESIw for the VT 1H-NMR
experiments on 3.
Fig. 7 X-Ray crystal structure of 32ꢄ[Sr(Picr)2]3 complex. (a) Top
view. Hydrogen atoms and picrates have been removed for clarity. (b)
Side view. Hydrogen atoms, picrates, and phenyl groups have been
omitted for clarity. Atom type: C gray, N blue, O red, Sr magenta.
peptoid, showed a unique all-trans peptoid bond configuration
(Fig. 7), with the carbonyl groups alternately pointing toward
the strontium cations and forcing the N-linked side chains to
assume an alternate pseudo-equatorial arrangement.
15 K. E. Koenig, G. M. Lein, P. Stuckler, T. Kaneda and D. J. Cram,
J. Am. Chem. Soc., 1979, 101, 3553.
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Chem. Commun., 2008, 3927–3929 | 3929