Self-assembled chiral dimeric capsules from difunctionalized N,C-linked peptidocalix[4]arenes: Scope and limitations

FULL PAPER

DOI: 10.1002/ejoc.200700943

Self-Assembled Chiral Dimeric Capsules from Difunctionalized N,C-Linked

Peptidocalix[4]arenes: Scope and Limitations

Laura Baldini,*^[a]Francesco Sansone,^[a]Giovanni Faimani,^[a]Chiara Massera,^[b]

Alessandro Casnati,^[a]and Rocco Ungaro*^[a]

Dedicated to Professor David N. Reinhoudt on the occasion of his 65th birthday

Keywords: Calixarenes / Hydrogen bonds / Chiral capsules / Self-assembly / Peptidomimetics

In this paper we report the synthesis of the first examples of

33 form hydrogen-bonded dimeric capsules in which the two

upper (wide) rim calix[4]arene amino acids 5 and 27, to- macrocycles approach each other face-to-face and rotated by

gether with the conformational, self-assembly and molecular

inclusion properties of the N,C-linked peptidocalix[4]arenes

obtained from them. Whereas the dipropyl derivative 5 read-

ily undergoes peptide synthesis allowing a small library of

calix[4]arene pseudopeptides 12–21 to be obtained, the tetra-

propoxy compound 27 preferentially gives upper-rim-

bridged derivatives (e.g., 28) which are formed through an

intramolecular condensation reaction. The tetrapropoxy-

calix[4]arene pseudopeptide 33 shows conformational and

self-assembly properties quite different to those of the di-

propoxy derivatives 12–21. The observed differences are ex-

plained on the basis of the different conformational flexibili-

ties of the two calix[4]arene scaffolds. Calixarene 5 is more

rigid than 27 thanks to the presence of two OH groups at the

lower (narrow) rim that are involved in strong intramolecular

hydrogen bonds. Only peptidocalix[4]arenes 12–21 but not

180° with respect to the other in order to allow hydrogen-

bonding complementarity between the interacting peptide

chains, which, in some cases (17–19), form an antiparallel β

sheet enhancing the stability of the capsule. The structures

of the chiral dimeric capsules were established by molecular

modelling calculations and NOESY NMR experiments,

which give consistent results, whereas their stability in

CDCl₃(69ՅK_dimՅ950

experiments. Compound 12 forms both 1:1 and 2:1 [K₁₁

M

^–1) was determined by dilution NMR

=

(7.8Ϯ1.2)ϫ10²

M M

^–1, K₂₁= (1.8Ϯ0.2)ϫ10^{5 –2}] host:guest com-

plexes with the methylpyridinium (MePy⁺) cation in CD₂Cl₂/

CDCl₃(10:1, v/v). There is no evidence for a guest template

effect in stabilizing the supramolecular capsule.

Germany, 2008)

subunits,^[2]that is, the functionalization of the calixarene

upper rim with appropriately positioned hydrogen-bonding

donor and acceptor groups.^[11]One famous example of

Introduction

The self-assembly of calix[4]arene derivatives in the cone

conformation through the interaction of suitable functional

groups on their upper (wide) rim may lead to the formation

of a capsular structure whose interior can accommodate a

guest.^[1,2]Non-covalent interactions such as ion-pairing,^[3–5]

metal–ligand coordination,^[6]hydrophobic interactions^[7]

and hydrogen bonding^[8–10]have been exploited to obtain

calixarene-based building blocks that self-assemble in

supramolecular capsules upon face-to-face dimerization.

The self-assembly of homodimeric calixarene capsules

through hydrogen bonding requires self-complementary

a

self-complementary calix[4]arene is Rebek’s^[8]and

Böhmer’s^[9]tetraurea derivative. Among Nature’s strategies

to obtain self-assembled structures, peptides play a major

role. In a reverse β sheet, for example, the amide groups are

specifically oriented to display self-complementarity. The

self-assembling propensity of peptides could be exploited to

obtain supramolecular capsules based on calixarenes if the

upper rim of the macrocycle could be functionalized with

amino acids or peptides in an appropriate orientation. With

the exception of a controversial and never confirmed pre-

liminary report^[12]and one example referring to a calix[6]-

arene derivative,^[13,14]C- and N-linked peptidocalixarenes

have not been exploited for the formation of chiral dimeric

capsules. On the other hand, we have recently shown that

difunctionalized C-linked peptidocalix[4]arenes form at the

solid state open tubular structures by self-assembly through

intermolecular hydrogen bonding.^[15,16]

[a] Dipartimento di Chimica Organica e Industriale, Università

degli Studi,

V. le G. P. Usberti, 17/A, 43100 Parma, Italy

E-mail: laura.baldini@unipr.it

rocco.ungaro@unipr.it

[b] Dipartimento di Chimica Generale ed Inorganica, Chimica

Analitica, Chimica Fisica, Universitá degli Studi,

V. le G. P. Usberti 17/A, 43100 Parma, Italy

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Eur. J. Org. Chem. 2008, 869–886

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A few years ago we reported in a short communication^[17]NH₂group linked to the calixarene aromatic nucleus com-

the synthesis of a calix[4]arene amino acid which allowed, pared with the aliphatic amine of an α-amino acid. None-

for the first time, the synthesis of N,C-linked peptidocalix- theless, 5 is quite stable both in the solid state and in solu-

[4]arenes able to form self-assembled dimeric capsules in a tion at neutral or acidic pH and in mildly basic conditions.

low polar medium. This paper provides a full account of a In contrast, a strongly basic solution leads to a slow degra-

more extensive study on this new class of peptidocalix[4]- dation of the product, easily visualized by the appearance

arenes and illustrates the scope and limitations of their self- of a pink-red colour. The degradation is presumably due to

assembly properties, together with their inclusion properties the oxidation of the p-NH₂aromatic nucleus to a benzo-

towards the methylpyridinium cation.

quinoneimine species which forms after the deprotonation

of the phenolic OH. As a consequence, in the peptide syn-

thesis (see below) the protection of the COOH group with

an alkyl ester had to be avoided as the deprotection step in

basic conditions leads to the formation of p-benzo-

quinoneimines.

Results and Discussion

Synthesis of Calix[4]arene Amino Acids and N,C-Linked

Peptidocalixarenes

The reaction of 5 with an N-protected amino acid/pep-

tide or propionic acid in the presence of the coupling rea-

gent HBTU leads to the formation of the intermediates 6–

11 which are characterized by the presence of a benzotri-

azolyl active ester on the calixarene carboxylic acid

(Scheme 2). During this coupling reaction no intra- or

intermolecular condensation reactions between the ArNH₂

and the active ester take place. The former reaction is pre-

vented by the presence of hydrogen bonds at the lower rim

which do not allow flattening of the cone and the formation

of an intramolecular amide bond (as was observed for the

analogous tetrapropoxy derivatives, see below), while the

latter is hindered by the low reactivity of the aromatic

amine group. The resulting benzotriazolyl active ester of the

carboxylic acid is also less reactive than the corresponding

group derived from a natural amino acid, thus ensuring the

stability of the intermediate during aqueous work-up and

chromatography on silica gel. Addition of the C-protected

amino acid/peptide in the presence of triethylamine and of

another equivalent of the coupling reagent (not strictly nec-

essary, but useful to improve the yield in case a small

The synthesis of the calix[4]arene amino acid 5 derived

from 1,3-dipropoxycalix[4]arene 1^[18]is depicted in

Scheme 1.

This methodology exploits the higher reactivity of ca-

lixarene phenolic nuclei relative to those of aryl ethers in

aromatic electrophilic substitution, which allows selectivity

to be transferred from the lower (narrow) rim to the upper

rim.^[19]Compound 1 was first mononitrated by using a con-

trolled excess of 65% HNO₃(1.8 equiv.) and then formyl-

ated on the opposite phenolic nucleus with dichloromethyl

methyl ether and SnCl₄. Subsequent oxidation of the formyl

group of 3 to a carboxylic acid and reduction of the nitro

group of 4 to an amine allowed the calix[4]arene amino acid

5 to be obtained in 23% overall yield from compound 1.

The mononitration of compound 1 is the step which re-

duces the yield of the whole process, all others giving very

high yields. The acid/base properties of the calixarene

amino acid 5 are rather different to those of the natural

ones. In fact, IR spectroscopy reveals that 5 is not present

in the zwitterionic form due to the lower basicity of the

Scheme 1.

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Eur. J. Org. Chem. 2008, 869–886

Chiral Dimeric Capsules from Peptidocalix[4]arenes

Scheme 2.

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871

L. Baldini, R. Ungaro et al.

FULL PAPER

Scheme 3.

amount of active ester hydrolysis takes place in the basic 27 having four propyl groups at the lower rim. After unsuc-

reaction medium) results in the formation of the N,C-linked cessful attempts to obtain compound 27 by alkylation of

peptidocalix[4]arenes 12–19 in satisfying (40–70%) yields. compound 4 by Mitsunobu reaction or of an N-protected

Overall, the protection/deprotection of the carboxylic derivative of 5 by direct reaction with n-propyl iodide in the

group, typical of classical peptide synthesis in solution, is presence of a base, we resolved to introduce the nitro and

not required and this is a big advantage of the described the formyl groups into the tetrapropoxycalixarene 22. We

synthetic protocol, which was also followed in the synthesis explored the two possible pathways: first the nitration and

of the amide derivatives 20 and 21. All compounds were then the formylation and vice versa (Scheme 3).

1

fully characterized by H and ¹³C NMR, ESI-MS and ele-

Mononitrotetrapropoxycalix[4]arene 23 is easily ob-

mental analyses.

tained in 55% yield by nitration of tetrapropoxycalix[4]-

In order to avoid the oxidation reactions of the p-ami- arene 22 following a literature procedure.^[20]The pure prod-

nophenol rings in basic conditions and to evaluate the im- uct is obtained by crystallization from CH₂Cl₂/MeOH. The

portance of the lower rim substitution on the self-assembly subsequent formylation yields a mixture of compounds

properties we also synthesized the calix[4]arene amino acid whose separation by column chromatography is tricky. We

succeeded in crystallizing the compound from the crude

Figure 2. Ball-and-stick representation of the hydrogen-bonding

Figure 1. Ball-and-stick representation of the hydrogen-bonding

motif in the crystal lattice of the imine derivative 27a (solvent mole-

cules and hydrogen atoms have been omitted for clarity; for a col-

oured picture see Figure S10 in the Supporting Information).

motif in the crystal lattice of 28 (non-hydrogen-bonded H atoms

have been omitted for clarity), viewed along two different directions

(for a coloured picture see Figure S11 in the Supporting Infor-

mation).

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Chiral Dimeric Capsules from Peptidocalix[4]arenes

mixture with CH₂Cl₂/hexane in 14% yield but, unfortu- 30% yield after column chromatography. During the reac-

nately, the conditions for obtaining the selective crystalli- tion, 10–15% cleavage of the propyl groups of the starting

zation of 25 are not easily reproducible. Therefore, even if material takes place. Nitration of 24 affords a crude mixture

the overall yield of this protocol is higher than the alterna- from which pure 25 can be isolated by column chromatog-

tive procedure (see below), we do not recommend it. Alter- raphy in 38% yield. The undesired 1,2-difunctionalized

natively, the monoformylation^[21]of 22 yields pure 24 in product is formed in 27% yield, and, considering that it has

Scheme 4.

Scheme 5.

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873

L. Baldini, R. Ungaro et al.

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a two-fold statistical factor, the formation of the 1,3-isomer Conformational and Self-Assembly Properties of N,C-

is significantly favoured. The 1,3-disubstitution pattern of Linked Peptidocalix[4]arenes

compound 25 is supported by ¹H and ¹³C NMR spec-

The two series of N,C-linked peptidocalix[4]arenes, one

derived from dipropoxycalix[4]arene amino acid 5 and the

other from the tetrapropoxy analogue 27, show quite dif-

ferent conformational and self-assembly properties which

troscopy and confirmed by X-ray diffraction studies (see

below). The subsequent oxidation of the formyl group and

reduction of the nitro group are carried out similarly to

literature procedures in high yields. As expected, during

highlight the important role played by hydrogen bonding at

these synthetic steps no oxidation of the aromatic nuclei

the lower rim of the calixarene.^[24]Compounds 12–21 show

takes place. Also compound 27, like the calix[4]arene amino

acid 5, exists in a non-zwitterionic form.

concentration-dependent ¹H NMR spectra in CDCl₃. In

the range 0.01–10 m the largest shifts are observed for the

A [D₆]acetone solution of compound 27, upon standing

ArNH, NHCbz and ArH (meta and para to the OPr group)

in an NMR tube, formed crystals suitable for crystallo-

protons. The NMR signals remain sharp and well-resolved

within the whole concentration range explored and indicate

the presence of a self-association equilibrium involving dis-

crete entities in fast exchange on the NMR time-scale, rul-

ing out the formation of disordered aggregates such as

oligomers or polymers. The self-association behaviour of

compounds 12–21 was therefore quantitatively investigated

through ¹H NMR dilution experiments in CDCl₃. The

shifts of several signals that could be easily followed during

the dilution experiment were simultaneously fitted to the

dimerization model by using the HypNMR program.^[25,26]

The non-linear regression analysis is in excellent agreement

with the model for all the compounds (see Figure 3 as an

example) and yielded the dimerization constants (K_dim) re-

ported in Table 1, along with the dimerization-induced

shifts (∆δ) of selected protons. Attempts to fit the observed

shifts to models including higher stoichiometry species were

unsuccessful, failing to attain convergence. The values of

the dimerization constants are in the range 10²–10³^–1and

generally increase with the number of hydrogen-bonding

groups present on the calixarene derivative. Moreover, in

graphic studies. X-ray diffraction analysis^[22]revealed that

the crystallized compound was in fact the imine derivative

27a which formed upon reaction with deuterated acetone

(Figure 1). One and a half solvent molecules per calixarene

unit are found in the crystal lattice, one of which is disor-

dered. In the crystal, the calixarene scaffold adopts a closed

flattened cone conformation with the Ar-imine and the Ar-

COOH rings almost parallel and the unsubstituted aro-

matic nuclei pointing outwards. This conformation is quite

unexpected since upper-rim 1,3-disubstituted calix[4]arenes

usually adopt an open flattened cone conformation in order

to reduce the steric hindrance between the two substitu-

ents.^[23]No intramolecular hydrogen bonding is present to

justify this conformation, which is probably induced by a

combination of intermolecular hydrogen bonds formed be-

tween the COOH and the imine nitrogen atom of neigh-

bouring molecules and crystal packing factors (Figure 1).

Functionalization of the tetrapropoxycalixarene amino

acid 27 to obtain a pseudopeptide was first carried out fol-

lowing the same synthetic protocol developed for the dipro-

poxy derivative 5. However, when 27 was treated with Cbz-

alanine in the presence of PyBOP and a base, the major

product was compound 28, derived from the intramolecular

reaction between the NH₂group and the COOH activated

by PyBOP (Scheme 4). The desired compound 29 was iso-

lated only in trace amounts.

In the NMR spectrum of 28, the aromatic protons ortho

to the CO and NH groups resonate at unusually high fields

(δ = 5.62 and 5.52 ppm, respectively) due to the highly flat-

tened structure of the compound, which was confirmed by

X-ray analysis.^[22]In the crystal, thanks to the unusual cis-

arrangement of the secondary amide bond, two molecules of

28 self-associate by means of two hydrogen bonds (Figure 2).

In contrast to the dipropoxy derivative 5, whose structure

is rigidified by the hydrogen bonds at the lower rim, the

flexible scaffold of 27 allows the formation of the intramo-

lecular condensation product even in the presence of the

scarcely nucleophilic aromatic amine group.

1

[D₆]DMSO the H NMR spectra of compounds 12–21 are

not concentration-dependent, while in [D₆]acetone smaller

variations of the chemical shifts during the dilution experi-

ments are observed.^[27]These data suggest that in CDCl₃

the dimerization process is driven by the formation of hy-

drogen bonds, presumably involving the ArNH and NHCbz

hydrogen-bonding donor groups.

To synthesize peptidocalixarene 33 and diamide 36, the

amino group of 27 had therefore to be protected. The Boc-

protected calixarene amino acid 30 was then condensed

with alanine methyl ester (or n-butylamine) in the presence

of PyBOP, the protecting group was removed with TFA

and, after reaction with Cbz-alanine (or propionic acid) in

the presence of PyBOP, the final products 33 and 36 were

obtained in good yields (Scheme 5).

Figure 3. Plot of the experimental chemical shifts of the ArNH (᭹),

ArH (meta OPr) (᭡), ArH (para OPr) (o), ArCONH (᭿) and

NHCbz (᭢) resonances of 21 during the ¹H NMR dilution experi-

ment (CDCl₃, 300 MHz, T = 298 K), along with the fitted curves

(plain lines).

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Chiral Dimeric Capsules from Peptidocalix[4]arenes

The ESI-MS spectra of 10^–4 solutions of compounds shown in Figure 4. Compound 20 is self-complementary in

12–21 in MeOH, both in the positive and in the negative terms of its hydrogen-bonding donor and acceptor groups

mode, are characterized by the presence of a peak corre- if two molecules approach each other “face-to-face”, with

sponding to the dimer with a relative abundance of 10–15% the ArCO nucleus facing the ArNH one. In the dimer the

relative to the monomer peak.

flattening of the calixarene scaffold (open flattened cone

Penta-pseudopeptides 17 and 18 and hepta-pseudopep- conformation) is necessary to allow the hydrogen-bonding

tide 19, having a higher number of hydrogen-bonding groups directly linked to the aromatic nuclei (ArNH and

groups, show association constants higher than the tri-pseu- ArCO) to get in close proximity to each other (Figure 4).

dopeptides 12–15. However, among compounds having the This structure is in agreement with the observed dimeriza-

same numbers of amino acids, significant variations in the tion-induced shifts and is also supported by the NOESY

association constants are observed. Comparison between NMR spectrum of compound 20 at high concentrations

the self-assembly properties of the different compounds of (Ͼ10^–2) which shows the presence of an intense cross-

this small library, along with a careful analysis of the NMR peak between ArNH and the aromatic protons ArHCO, to-

spectra during the dilution experiments, proved helpful in gether with a smaller correlation between the aromatic pro-

investigating the structural features of the self-assembled di- tons ArHCO and ArHNH which are held in close proxim-

mers. Remarkably, the dimerization-induced shifts of the ity by the ArNH···OCAr interaction (see Figure S3, Sup-

signals that experience the largest variations are generally porting Information).^[28]

conserved throughout the series (Table 1), indicating that

the structure of the dimer is essentially the same for all the

compounds. The amide groups directly linked to the aro-

matic nuclei (ArNHCO and ArCONH) are the only hydro-

gen-bonding groups that are present in all the compounds

and must therefore be primarily responsible for the self-as-

sembly. When other hydrogen-bonding groups are present

they can contribute to the dimer stability through ad-

ditional interactions. ArNH is the signal that undergoes the

largest upfield shift upon dimer formation (∆δ in the range

2.0–2.9 ppm, Table 1), indicating that it is involved in a

strong hydrogen bond. Therefore, the hydrogen-bond ac-

ceptor must be the ArCO group. The small downfield shift

(0.3–0.6 ppm) observed for the ArCONH protons is proba-

bly just a consequence of its proximity to the hydrogen-

see Figure S12 in the Supporting Information).

bonding acceptor ArCO group. Besides ArNH, the second

Figure 4. Lateral (left) and top (right) view of a molecular model

(MMFF) of the self-assembled dimer of 20 (for a coloured picture

most shifted signals during the dilution experiments are

In peptidocalixarenes 12–15 and 21, the significant

those of the ArH protons meta and para to the OPr groups, downfield shift experienced by the NHCbz (or the corre-

which are upfield-shifted (∆δ in the range –2.0 to –1.6 and sponding NHAc for 15) resonance upon dimerization (∆δ

–1.3 to –1.0 ppm for the para and meta protons, respec- in the range 1.4–0.6 ppm) indicates that also this group acts

tively). The upfield shift implies that the calixarene confor- as a hydrogen-bond donor, while the small downfield shift

mation in the dimer is more flattened than in the monomer, (0.6–0.3 ppm) observed for the NH of the N-linked amino

with the unfunctionalized aromatic rings pointing inwards acid (or amide) is probably just a consequence of its prox-

into the shielding cone of the other two amide-function- imity to the hydrogen-bonding acceptor ArCO group. The

alized phenolic nuclei. A minimized structure obtained is temperature coefficients measured for the NH signals of

Table 1. Dimerization constants and dimerization-induced shifts (∆δ = δ_dimer– δ_monomer) for the self-association of compounds 12–21.^[a]

K_dim[^–1]

∆δ [ppm]

[b]

Compound

ArNH

NHCbz

ArCONH

ArH (p-OPr)

ArH (m-OPr)

12

13

14

15

16

17

18

19

20

21

105

115

69

2.3

2.6

2.5

2.0

n.d.

1.5

2.9

2.7

0.8

0.9

0.8

0.4

0.3

0.4

0.6

0.4

n.d.

0.4

–1.8

–2.0

–1.9

–1.6

n.d.

–1.8

–2.0

–1.2

–1.3

–1.2

–1.0

n.d.

–0.9

–1.2

–1.3

79

0.8^[c]

0.7^[d]

n.d.

0.6

110

788

466

950

74

0.8

–

1.4

169

0.4

[a] Measured by ¹H NMR (300 MHz, CDCl₃) dilution experiments in the concentration range 10^–2–10^–5 at T = 298 K; n.d. = not

determined because the proton signal is superimposed by others. [b] Errors between 2–15%. [c] ∆δ(NHAc). [d] ∆δ[ArNHCOCH(CH₃)-

NH].

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875

L. Baldini, R. Ungaro et al.

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Figure 5. Top views of the molecular models (MMFF) of the self-assembled dimers of 21 (left) and 17 (right). The butyl chain and the

benzyl group of 21 and the alanine methyl groups and the benzyl group of 17 have been omitted for clarity (for a coloured picture see

Figure S13 in the Supporting Information).

compound 12 reflect the different degree of hydrogen-bond- in the steric hindrance of the lateral groups. The known

ing involvement of these protons: ArNH (–17 ppbK^–1) Ͼ higher tendency^[30]for peptides having lipophilic side-

NHCbz (–6.2 ppbK^–1) Ͼ ArCONH (–3.1 ppbK^–1).^[29]Mo- chains to form β sheets in water cannot operate in chloro-

lecular modelling of compound 21 (Figure 5, left) and 12 form and the steric hindrance predominates in this solvent.

(see Figure S4 in the Supporting Information) reveals that Finally, the longest member of this library, the hepta-pseu-

in both compounds only a bifurcated hydrogen bond be- dopeptide 19, dimerizes with an association constant that

tween both NH donor groups of the C-linked amino acids is only 17% larger than the penta-pseudopeptide 17, and it

and the ArCO acceptor unit is formed in spite of the fact shows slightly broad NMR spectra even at low concentra-

that in the tri-pseudopeptide 12 a second CO acceptor tion. This indicates that by increasing the number of hydro-

group is also present. This explains the relatively high di- gen-bonding groups, additional interactions, either intra- or

merization constant shown by 21 (nearly double that of 20) intermolecular, take place and, besides the dimerization,

and the large downfield shift ∆δ = 1.4 ppm of the NHCbz oligomerization processes can also occur.

proton observed upon 21₂dimer formation.

In contrast to the dipropoxy peptidocalixarenes de-

The smaller dimerization constants of 12–15 compared scribed above, the tetrapropoxy derivatives 33 and 36 do

with 21 (Table 1) confirm that the larger steric hindrance not self-aggregate in the concentration range 0.01–10 m.

1

given by the N-linked amino acid side-chain disfavours self- The H NMR spectra of these compounds in fact are not

assembly. The phenylalanine derivative 14, in fact, displays dependent on the concentration. Instead, compound 33

the smallest dimerization efficiency among the tri-pseudo- adopts in CDCl₃a closed flattened cone conformation with

peptides. Also the NOESY NMR spectra of the peptidoca- the substituted aromatic rings pointing inwards, as deduced

lixarenes 12, 15 and 21 show cross-peaks between the from the relative position of the signals of the aromatic pro-

ArNH and ArHCO protons and between the ArHNH and tons in the NMR spectrum: δ = 6.86 and 6.75 ppm for

ArHCO aromatic protons (see Figures S5–S7, Supporting ArH(CO), 6.39 and 6.28 ppm for ArH(NH) and 6.80–

Information). The seven-fold increase in the association 6.70 ppm for the non-substituted ArH. This structure is due

constant measured for the penta-pseudopeptide 17 with re- to the formation of an intramolecular hydrogen bond which

spect to 12 can be easily explained by an increase in the is confirmed by the presence in the NOESY spectrum of a

number of hydrogen-bonding interactions. Interestingly, the cross-peak between the CH protons of the two alanine

NOESY NMR spectrum of 17 shows a correlation peak chains. In [D₆]acetone, on the other hand, the hydrogen

between two CH protons, one belonging to the N-linked bond is broken and the conformation adopted is an open

and the other to the C-linked peptide, in addition to the flattened cone with the alanine chains pointing outwards [δ

ArNH–ArHCO cross-peak (see Figure S8, Supporting In- = 7.61 ppm for ArH(CO), 7.27 and 7.22 ppm for the two

formation). A molecular modelling (MMFF) study yielded signals of ArH(NH) and 6.40–6.34 ppm for ArH, Figure 6].

as the minimum energy conformer the dimer represented

The diamide 36 in CDCl₃also adopts a closed flattened

in Figure 5 (right) in which, in addition to the bifurcated cone conformation induced by the formation of an intra-

interactions found in the pseudopeptides 12–15 and 21, a molecular hydrogen bond. The larger temperature coeffi-

hydrogen bond between the CO(Cbz) and the NH of the cient^[29]of the ArNH with respect to the ArCONH amide

terminal alanine methyl ester is also present. This model proton NMR chemical shifts (–4.7 vs. –2.2 ppbK^–1, respec-

substantiates the proximity of the two alanine CH protons tively) and the presence of a cross-peak in the NOESY spec-

of the two different chains and the resulting NOE corre- trum between COCH₂and NHCH₂and between ArNH

lations. Moreover, this additional interaction, together with and ArH(CO) suggest that the intramolecular interaction is

the NH(alanine)···OCAr hydrogen bond, forms a 14-mem- formed between ArNH as hydrogen-bond donor and ArCO

bered ring typical of a peptide β sheet. On the other hand, as acceptor. In [D₆]acetone this hydrogen bond is broken,

the tetra-pseudopeptide 16, which lacks the second NH in as deduced from the relative signal positions of the aromatic

the N-linked chain, self-assembles with the same efficiency protons [ArH(CO): 7.29, ArH(NH): 6.89, ArH: 6.50 ppm]

1

as 12 and with a lower efficiency than 17 since it forms only in the H NMR spectrum. The involvement of the hydro-

two bifurcated hydrogen bonds. Even though it has the gen-bonding groups in intramolecular interactions there-

same number of amino acids as 17, compound 18 self-as- fore prevents the formation of self-assembled dimers, as ob-

sembles with less efficiency than 17 because of an increase served for the dipropoxypeptidocalixarenes. In turn, the in-

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Chiral Dimeric Capsules from Peptidocalix[4]arenes

1

Figure 6. H NMR spectra (top: 300 MHz, CDCl₃, T = 298 K; bottom: 300 MHz, [D₆]acetone, T = 298 K) of compound 33 showing

the relative positions of the signals of the aromatic protons ArH(CO) (᭹), ArH(NH) (᭿) and ArH (unsubstituted ring) (᭡).

tramolecular interactions take place thanks to the tetra- break down the cage and release the guest, all the signals

propoxycalix[4]arene scaffold which is more flexible than of MePy⁺are clearly visible at lower fields. By integration

those of the dipropoxy derivatives. For the latter com- of the signals of MePy⁺relative to the calixarene, 33%

pounds, in fact, the strong hydrogen bonds at the lower rim guest extraction (with respect to 12) was determined. The

between the phenolic OH and O propoxy groups, impart ESI-MS spectra (both in methanol and dichloromethane)

sufficient rigidity on the calixarene scaffold to prevent the of the filtered solution showed the presence of peaks corre-

formation of intramolecular interactions.^[24]

sponding to both the complexes 12₂·MePy⁺and 12·MePy⁺.

The same experiment performed on compounds 17 and 20

yielded a 17% MePyPF₆extraction in both cases. To mea-

Complexation Properties

1

sure the formation constants of the complexes a H NMR

titration was performed with methylpyridinium tetrakis-

(pentafluorophenyl)borate as the guest in CD₂Cl₂/CDCl₃

(10:1, v/v). The tetrakis(pentafluorophenyl)borate anion

was chosen for solubility reasons, the absence of aromatic

protons and because it forms a loose ion-pair with MePy⁺.

Upon addition of a concentrated solution of the guest to a

0.027  solution of the host, complexation-induced shifts in

The molecular modelling studies performed on the self-

assembled capsules derived from 12–21 reveal that they

have an internal volume of around 150 Å³.^[17]To assess

whether the inner cavity is available for guest encapsulation

we studied the complexation ability of 12₂, 17₂and 20₂di-

mers towards the methylpyridinium (MePy⁺) cation, a suit-

able guest in terms of size and electronic features for di-

meric calixarene-based cages.^[31,32]In order to follow the

1

the H NMR spectra were observed for all the resonances

of MePy⁺and for several of the host signals. In particular,

all the signals of the guest were initially upfield-shifted with

respect to their resonance in the absence of calixarene (δ =

2.15 vs. 4.40 ppm for the methyl group, 6.20 vs. 8.52 ppm

for the PyH-ortho and 6.10 vs. 8.08 ppm for the PyH-meta),

a clear indication of the binding of MePy⁺within the aro-

matic cavity of the dimeric capsule. During the titration

their signals moved gradually to lower fields. Equilibrium

is rapid on the NMR time-scale and the observed chemical

shifts are a weighted average of the shifts of the nuclei in

all the species present at equilibrium. The host and guest

signals that were unequivocally identified were simulta-

neously fitted to the model in Scheme 6^[33]using

HypNMR.^[25]The dimerization constant K_dimof 12 in

CD₂Cl₂/CDCl₃(10:1, v/v) was independently measured in

1

binding experiments by H NMR in CDCl₃, we required a

counterion which formed a loose ion-pair with the cation

and whose resonances possibly did not interfere with the

¹H NMR spectra of the peptidocalixarenes. Therefore we

initially evaluated whether concentrated CDCl₃solutions of

dimers 12₂, 17₂and 20₂were able to extract solid MePyPF₆,

1

which is insoluble in this solvent. The H NMR spectrum

of a 10 m CDCl₃solution of 12 stirred for a few hours

in the presence of solid MePyPF₆and filtered to remove

undissolved salt shows the presence of peaks belonging to

the MePy⁺cation. The methyl group is clearly visible as a

singlet at δ = 2.59 ppm (∆δ = –2.0 ppm), while the reso-

nances of the pyridinium ring partly overlap the calixarene

signals in the region 9.87–6.32 ppm, upfield-shifted by

around 1.7–2 ppm with respect to free methylpyridinium to-

sylate [MePy(Tos)] in CDCl₃, thus indicating encapsulation

of the guest. After the addition of 200 µL of [D₆]acetone to

a

¹H NMR dilution experiment and was found to be

38(Ϯ0.4) ^–1(see Figure S9, Supporting Information). This

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877

L. Baldini, R. Ungaro et al.

FULL PAPER

value was included as an invariant in the non-linear re- of hydrogen-bonding donor and acceptor groups if the

gression analysis which gave a good fit to the model (Fig- structure assumes a pseudo-β-sheet conformation. Dimer-

ure 7), with errors in the calculated chemical shifts of the ization can thus be achieved when two molecules approach

1:1 and 2:1 complexes of Ͻ0.08 ppm. The calculated associ- each other “face-to-face” and rotated by 180° with respect

ation constants K₁₁= (7.82Ϯ1.2)ϫ10²^–1and K₂₁

=

to the other. Upon hydrogen-bond formation, the aromatic

(1.77Ϯ0.2)ϫ10⁵^–2allowed the species distribution during cavities of the two calixarene molecules in the dimer are

1

the H NMR titration to be determined (Figure 7).

held in strong contact and surround an enclosed space, as

1

proved by H NMR and confirmed by the ability of the

dimer to encapsulate a guest. The stability of the dimeric

capsule increases by increasing the number of amino acid

units up to a certain level when other intermolecular self-

association motives leading to polymers prevail.

An interesting finding of this work is the disclosure of

the important role played by the two OH groups at the

lower rim of the calix[4]arenes which reduce the conforma-

tional flexibility of the macrocycle through hydrogen bond-

ing thus controlling both the outcome of the synthetic

transformations and the self-assembly properties of this

new class of synthetic receptor.

The capsular supramolecular assembly formed through

the action of enantiomerically pure peptide chains creates

a partially enclosed chiral space^[38]that is potentially cap-

able of enantioselective recognition.^[39]This possibility has

not been investigated yet since our first aim was to learn

about the molecular rules that regulate the self-assembly

processes in N,C-linked peptidocalix[4]arenes. However, in

order to investigate the chiral recognition properties of the

capsule it will be necessary to enhance both its kinetic and

thermodynamic stability and reduce the size of the openings

which allow guests to escape from the interior. This will

require, as in classical tetraurea calix[4]arenes, the synthesis

of calix[4]arene subunits bearing four peptide chains at the

upper rim, while maintaining two OH groups at the lower

rim. The feasibility of such a synthesis is currently under

Scheme 6. Model for the association of 12 with MePy⁺.

Figure 7. Complexation-induced shifts of the NHAr (᭡) and the study in our laboratory.

PyH-ortho (ϫ) resonances of 12 and MePy⁺, respectively, together

with the best fit curves obtained through nonlinear regression

analysis (- - -) and the simulated concentration profiles (–––) for

the species involved in the equilibria of Scheme 6.

Experimental Section

General Methods: All reactions were carried out under nitrogen.

1

During the H NMR titration, the maximum amount of

Dry solvents were prepared according to standard procedures and

stored over molecular sieves. Melting points were determined under

the filled capsule 12₂·MePy⁺(47.5%, relative to 12, Fig-

ure 7) is reached when the total concentrations of 12 and

MePy⁺are 0.020 and 0.011 , respectively. At this point,

6% of the empty dimer 12₂is also present. In the absence

1

nitrogen in sealed capillaries with an Electrothermal apparatus. H

and ¹³C NMR spectra were recorded at 300 and 75 MHz, respec-

tively, on Bruker AV300 and AC300 spectrometers (partially de-

of guest, at the same concentration of 12 (0.02 ), the uteriated solvents were used as internal standard). Mass spectra

were registered in ESI and CI (CH₄) mode with Micromass ZMD

and Finnigan Mat SSQ710 spectrometers, respectively. Optical ro-

tations were measured at 20 °C with a Perkin-Elmer 241 Polarime-

ter using a wavelength of 589 nm. [α]_Dvalues are given in

10^–1degcm²g^–1. Elemental analyses were performed using a CHN

1106 Carlo Erba instrument and are reported as percentages. TLC

was performed on silica gel Merck 60 F254 sheets and flash

chromatography on 230–240 mesh Merck 60 silica gel. Amino acids

were purchased from Sigma.

amount of capsule 12₂is 45%, as calculated from the K_dim

of 12 in CD₂Cl₂/CDCl₃(10:1, v/v) (see Figure S9, Support-

ing Information). This implies that the guest shows a good

affinity towards the capsule enclosed space but does not

display an important template effect on capsule formation

as observed in other cases.^[34–37]

Conclusions

For reasons of clarity and in order to reduce space, the name ca-

lix[4]arene has been used instead of the full IUPAC name: penta-

cyclo[19.3.1.1^3,7.1^9,13.1^15,19]octacosa-1(25),3,5,7(28),9,11,13(27),

Peptidocalix[4]arenes 12–21 are essentially pseudopep-

tides incorporating an unnatural calix[4]arene amino acid

and therefore are intrinsically self-complementary in terms 15,17,19(26),21,23-dodecene.

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Chiral Dimeric Capsules from Peptidocalix[4]arenes

¹H NMR Experiments for the Determination of the Dimerization

temp. for 18 h and the solvent evaporated to dryness at reduced

pressure. Then 1  HCl (20 mL) was added to give 4 as a pale

yellow solid which was crystallized from Et₂O. Yield 0.9 g,

1

Constant: H NMR spectra were recorded for a series of samples

of increasing concentrations of peptidocalixarene from 5ϫ10^–5

up to 1.0ϫ10^–2.



1

1.48 mmol, 86%. M.p. 325–328 °C. H NMR (300 MHz, CDCl₃):

δ = 9.49 (s, 1 H, OH), 9.06 (s, 1 H, OH), 8.03 (s, 2 H, ArH), 7.86

(s, 2 H, ArH), 7.00 (dd, J = 7.5, 1.8 Hz, 2 H, ArH), 6.96 (dd, J =

7.5, 1.8 Hz, 2 H, ArH), 6.82 (t, J = 7.5 Hz, 2 H, ArH), 4.29 (d, J

= 12.9 Hz, 2 H, H_axof ArCH₂Ar), 4.27 (d, J = 12.9 Hz, 2 H, H_ax

of ArCH₂Ar), 4.08–3.98 (m, 4 H, OCH₂), 3.49 (d, J = 12.9 Hz, 4

H, H_eqof ArCH₂Ar), 2.17–1.98 (m, 4 H, OCH₂CH₂), 1.32 (t, J =

7.2 Hz, 6 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 171.6 (s,

CO), 159.7, 158.7, 151.7, 139.7, 132.7, 131.6, 131.1, 129.7, 129.1,

128.4, 127.8, 125.7, 124.5, 119.1 (Ar), 78.6 (t, OCH₂), 31.2 (t, Ar-

CH₂Ar), 23.4 (t, OCH₂CH₂), 10.8 (q, CH₃) ppm. MS-CI: m/z (%)=

597.8 (80) [M]⁺, 580 (100) [M – OH]⁺. C₃₅H₃₅NO₈(597.23): calcd.

C 70.34, H 5.90, N 2.34; found C 70.51, H 6.01, N 2.28.

¹H NMR Titration Experiment for the Determination of the Associ-

ation Constants of 12 and 12₂with MePy⁺: A solution of methylpyr-

idinium tetrakis(pentafluorophenyl)borate (41 m, 1.5 mL) in

CD₂Cl₂/CDCl₃(10:1, v/v) was added in small aliquots to a 27 m

solution of 12 (0.5 mL) and the ¹H NMR spectra were recorded

after each addition. Mathematical analysis of data and graphical

presentation of results were performed using the program

HypNMR2004 (v. 3.1.42).^[40]

Extraction of Solid MePyPF₆: A solution of the peptidocalixarene

[12 (10 m), or 17 (5 m) or 20 (5 m); 1 mL] in CDCl₃was stirred

overnight in the presence of MePyPF₆(20 mg). The solution was

filtered and the ¹H NMR spectrum of the filtrate was recorded

using 0.5 mL of solution. A blank experiment in the absence of

peptidocalixarene was performed to ensure the insolubility of Me-

PyPF₆in the solvent. The amount of MePy⁺extracted was deter-

mined by integration of the signals of MePy⁺with respect to the

calixarene after addition of [D₆]acetone (0.2 mL).

11-Amino-25,27-dihydroxy-26,28-dipropoxycalix[4]arene-23-carbox-

ylic Acid (5): Hydrazine hydrate (0.40 mL, 8.36 mmol) and a cata-

lytic amount of Pd/C (10 %) were added to a suspension of 4

(250 mg, 0.418 mmol) in ethanol (25 mL). The mixture was stirred

for 3 h at 60 °C, then the catalyst was filtered off rapidly under

nitrogen. The organic solvent was evaporated under reduced pres-

sure to obtain the product as a white solid, to be used without

further purification. Yield 0.17 g, 0.30 mmol, 70 %. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 9.21 (s, 1 H, OH), 7.78 (s, 2 H, ArH),

7.62 (s, 1 H, OH), 7.04 (d, J = 7.8 Hz, 2 H, ArH), 7.02 (d, J =

7.8 Hz, 2 H, ArH), 6.80 (t, J = 7.4 Hz, 2 H, ArH), 6.38 (s, 2 H,

ArH), 4.16 (d, J = 12.9 Hz, 2 H, H_axof ArCH₂Ar), 4.14 (d, J =

1 2 . 3 H z , 2 H , H _{a x}o f A r C H ₂A r ) , 4 . 0 3– 3 . 8 8 ( m , 4 H ,

OCH₂CH₂CH₃), 3.56 (d, J = 12.9 Hz, 2 H, H_eqof ArCH₂Ar), 3.24

(d, J = 12.3 Hz, 2 H, H_eqof ArCH₂Ar), 2.09–1.91 (m, 4 H,

OCH₂CH₂CH₃), 1.29 (t, J = 7.4 Hz, 6 H, OCH₂CH₂CH₃) ppm.

¹³C NMR (75 MHz, [D₆]DMSO): δ = 167.2 (s, CO), 157.2, 151.7,

134.1, 133.1, 130.3, 129.0, 128.9, 128.2, 127.8, 125.3, 121.4, 115.9

(Ar), 78.1 (t, OCH₂CH₂CH₃), 30.6, 30.4 (t, ArCH₂Ar), 23.1

11-Nitro-25,27-dihydroxy-26,28-dipropoxycalix[4]arene (2): HNO₃

(65 % solution, 0.5 mL, 7.2 mmol) was added to a solution of

25,27-dihydroxy-26,28-dipropoxycalix[4]arene (1)^[18](2.0 g,

3.9 mmol) in CH₂Cl₂(200 mL) and acetic acid (2 mL). The reac-

tion mixture was stirred for 45 min at room temp., quenched by

addition of a NaHCO₃saturated solution (150 mL) and vigorously

stirred for 10 min. The organic layer was separated, washed with

distilled water (2ϫ150 mL), dried with MgSO₄and the solvents

evaporated to dryness at reduced pressure. The crude was purified

by flash chromatography (eluent: hexane/CH₂Cl₂, 2:1, v/v) to ob-

tain the product as pale yellow solid. Yield 0.97 g, 1.8 mmol, 45%.

1

M.p. 277–278 °C. H NMR (300 MHz, CDCl₃): δ = 9.52 (s, 1 H,

OH), 8.22 (s, 1 H, OH), 8.03 (s, 2 H, ArH), 7.06 (d, J = 7.5 Hz, 2

H, ArH), 6.98, 6.94 (2dd, J = 7.5, 1.5 Hz, ArH, 2H each), 6.79 (t,

J = 7.5 Hz, 2 H, ArH), 6.66 (t, J = 7.5 Hz, 1 H, ArH), 4.31 (d, J

= 13.2 Hz, 2 H, H_axof ArCH₂Ar), 4.30 (d, J = 13.0 Hz, 2 H, H_ax

of ArCH₂Ar), 4.07–3.93 (m, 4 H, OCH₂CH₂CH₃), 3.48 (d, J =

13.2 Hz, 2 H, H_eqof ArCH₂Ar), 3.40 (d, J = 13.0 Hz, 2 H, H_eqof

ArCH₂Ar), 2.14–2.00 (m, 4 H, OCH₂CH₂CH₃), 1.32 (t, J = 7.4 Hz,

6 H, OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 159.9,

153.2, 151.8, 139.6, 133.6, 131.6, 129.7, 128.8, 128.6, 128.5, 127.7,

125.5, 124.5, 114.1 (Ar), 78.5 (t, OCH₂CH₂CH₃), 31.3 (t, Ar-

CH₂Ar), 23.4 (t, OCH₂CH₂CH₃), 10.8 (q, OCH₂CH₂CH₃) ppm.

MS (CI-MS): calcd. for C₃₄H₃₅NO₆553.2; found 554.4 [M + H]⁺.

C₃₄H₃₅NO₆(553.66): calcd. C 73.76, H 6.37, N 2.53; found C

73.82, H 6.21, N 2.42.

(OCH CH CH ), 10.8 (OCH CH CH ) ppm. IR (KBr): ν = 3358

˜

2

3

2

3

(NH, OH), 1674 (CO) cm^–1. MS-ESI: m/z (%) = 590.3 (100) [M +

Na]⁺. C₃₅H₃₇NO₆(567.26): calcd. C 74.05, H 6.57, N 2.47; found

C 74.22, H 6.63, N 2.38.

General Procedure for the Synthesis of Intermediates 6–9 and 11:

The calixarene 5 (100 mg, 0.18 mmol), the appropriate N-protected

amino acid or dipeptide or propionic acid (0.35 mmol) and NEt₃

(1.2 mL, 0.88 mmol) were mixed in dry CH₂Cl₂(10 mL). Then

HBTU (240 mg, 0.63 mmol) was added and the reaction mixture

was stirred at room temp. for 2–5 h. The reaction was quenched by

addition of distilled water, the organic layer separated and the sol-

vents evaporated to dryness at reduced pressure.

11-Nitro-23-formyl-25,27-dihydroxy-26,28-dipropoxycalix[4]arene

(3): Cl₂CHOCH₃(0.49 mL, 5.43 mmol) and SnCl₄(2.12 mL,

18.1 mmol) were added to a solution of 2 (1 g, 1.81 mmol) in dry

CHCl₃(30 mL), cooled to –13 °C. The reaction was then stirred for

3 h at room temp., quenched by addition of 1  HCl and vigorously

stirred for 20 min. The organic layer was separated, washed with

distilled water until neutral pH and the solvents evaporated to dry-

ness under reduced pressure to achieve 3 as a solid. Yield 0.89 g,

1.5 mmol, 85%. All the spectroscopic data resulted in agreement

with those previously reported.^[41]

11-(N-Cbz-L-Alanyl)amino-23-benzotriazolyloxycarbonyl-25,27-di-

hydroxy-26,28-dipropoxycalix[4]arene (6): The crude was purified

by flash column chromatography (eluent: hexane/AcOEt, 1:1) to

obtain the product as a white solid. Yield 113 mg, 0.13 mmol, 72%.

M.p. 170–173 °C. [α]²_D⁰= –17.7 (c = 0.84, in CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 9.50 (s, 1 H, OH), 9.19 (s, 1 H, OH), 8.13

(br. s, 1 H, ArNH), 8.07 (d, J = 8.2 Hz, 1 H, ArH), 8.04 (s, 2 H,

ArH), 7.51–7.37 (m, 3 H, ArH), 7.31–7.27 (m, 7 H, ArH), 6.88–

6.95 (m, 4 H, ArH), 6.70 (t, J = 7.5 Hz, 2 H, ArH), 5.47 (br. s, 1 H,

NHCbz), 5.15 (d, J = 12.2 Hz, 1 H, CH₂Ph), 5.09 (d, J = 12.2 Hz, 1

H, CH₂Ph), 4.39 (br. s, 1 H, CHCH₃), 4.34 (d, J = 12.9 Hz, 2 H,

H_axof ArCH₂Ar), 4.29 (d, J = 13.2 Hz, 2 H, H_axof ArCH₂Ar),

3.99 (br. s, 4 H, OCH₂CH₂), 3.51 (d, J = 13.2 Hz, 2 H, H_eqof

ArCH₂Ar), 3.35 (d, J = 12.9 Hz, 2 H, H_eqof ArCH₂Ar), 2.05–2.15

(m, 4 H, OCH₂CH₂), 1.44 (d, J = 6.6 Hz, 3 H, CHCH₃), 1.25–1.40

25,27-Dihydroxy-11-nitro-26,28-dipropoxycalix[4]arene-23-carb-

oxylic Acid (4): A solution of 3 (1 g, 1.72 mmol) in CHCl₃/acetone

(60 mL, 1:1, v/v) was cooled to 0 °C and treated with an aqueous

solution (15 mL) of H₂NSO₃H (545 mg, 5.62 mmol) and NaClO₂

(342 mg, 3.78 mmol). The mixture was vigorously stirred at room

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879

L. Baldini, R. Ungaro et al.

FULL PAPER

(m, 6 H, CH₂CH₃) ppm. ¹³C NMR (75 MHz, [D₆]acetone): δ =

(d, J = 13.2 Hz, 2 H, H_eqof ArCH₂Ar), 3.39 (d, J = 12.9 Hz, 2 H,

171.1, 163.5 and 161.5 (CO), 152.8, 150.5, 144.3, 134.7, 133.4, H_eqof ArCH₂Ar), 2.10–2.05 (m, 6 H, OCH₂CH₂, and 2 CH), 1.67

132.3, 131.4, 131.3, 130.3, 130.0, 129.8, 129.6, 129.1, 128.7, 128.6,

126.2, 125.7, 121.2, 121.1, 120.8, 115.5 and 109.7 (Ar), 79.3

(OCH₂CH₂), 66.8 (CH₂Ph), 52.0 (CHCH₃), 31.8 and 31.4 (Ar-

CH₂Ar), 24.2 (OCH₂CH₂), 18.8 (CHCH₃), 11.3 (CH₂CH₃) ppm.

ESI-MS: m/z (%) = 912.3 (100) [M + Na]⁺. C₅₂H₅₁N₅O₉(889.37):

calcd. C 70.18, H 5.78, N 7.87; found C 70.24, H 5.89, N 7.82.

(br. s, 2 H, CH₂Leu), 1.61–1.49 (m, 2 H, CH₂), 1.33 (t, J = 7.2 Hz,

6 H, CH₂CH₃), 0.96–0.83 (m, 12 H, CH₃) ppm. ESI-MS: m/z (%)

= 965.1 (95) [MOCH₃+ Na]⁺,^[42]1068.1 (100) [M + Na]⁺.

C₆₁H₆₈N₆O₁₀(1044.50): calcd. C 70.10, H 6.56, N 8.04; found C

70.12, H 6.47, N 8.09.

23-Benzotriazolyloxycarbonyl-25,27-dihydroxy-11-propanoylamino-

26,28-dipropoxycalix[4]arene (11): The crude was purified by flash

column chromatography (eluent: hexane/AcOEt, 11:14) to obtain

the product as a white solid. Yield 73 mg, 0.10 mmol, 55%. M.p.

11-[N-Acetyl-(dl)-leucyl]amino-23-benzotriazolyloxycarbonyl-25,27-

dihydroxy-26,28-dipropoxycalix[4]arene (7): The crude was purified

by flash column chromatography (eluent: CH₂Cl₂/MeOH, 95:5) to

obtain the product as a white solid. Yield 36 mg, 0.04 mmol, 24%.

¹H NMR (300 MHz, CDCl₃): δ = 9.53 (s, 1 H, OH), 8.27 (s, 1 H,

ArNH), 8.22 (s, 1 H, OH), 8.08 (d, J = 8.3 Hz, 1 H, ArH), 8.02 (s,

2 H, ArH), 7.52–7.39 (m, 3 H, ArH), 7.29 (d, J = 2.5 Hz, 1 H,

ArH), 7.25 (d, J = 2.5 Hz, 1 H, ArH), 7.00–6.94 (m, 4 H, ArH),

6.81–6.75 (m, 2 H, ArH), 6.13 (br. s, 1 H, NH), 4.67–6.61 (m, 4 H,

H_axof ArCH₂Ar), 4.60 (br. s, 1 H, CH), 4.35–4.26 (m, 4 H,

OCH₂CH₂), 3.49 (d, J = 13.2 Hz, 2 H, H_eqof ArCH₂Ar), 3.36 (d,

J = 13.0 Hz, 2 H, H_eqof ArCH₂Ar), 2.11–2.00 (m, 4 H,OCH₂CH₂),

2.01 (s, 3 H, COCH₃), 1.67–1.51 (m, 3 H, CH and CH₂) 1.32 (t, J

= 7.5 Hz, 3 H, CH₂CH₃), 0.95 (s, 6 H, CH₃) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 173.7 (CO), 170.7 (CO), 169.4 (CO), 162.5,

160.6, 151.7, 150.09, 133.3, 131.3, 131.7, 129.5, 129.1, 128.9, 128.4,

128.1, 125.5, 124.6, 120.4, 108.6 (Ar), 78.5 (CH₂CH₃), 50.6, 41.6,

31.3 (ArCH₂Ar), 24.8, 23.4, 22.7, 21.9, 10.8 ppm. ESI-MS: m/z (%)

= 759.7 (100), [MOCH₃+ Na]⁺,^[42]862.7 (49) [M + Na]⁺.

C₄₉H₅₃N₅O₈(839.39): calcd. C 70.06, H 6.36, N 8.34; found C

70.15, H 6.30, N 8.41.

1

191 °C (decomp.) H NMR (300 MHz, CDCl₃): δ = 9.50 (s, 1 H,

OH), 8.16 (s, 1 H, OH), 8.07 (d, J = 8.8 Hz, 1 H, ArH), 8.03 (s, 2

H, Ar), 7.54–7.36 (m, 3 H, ArH), 7.27 (s, 2 H, ArH), 7.12 (s, 1 H,

NH), 7.03–6.88 (m, 4 H, ArH), 6.73 (t, J = 7.5 Hz, 2 H, ArH),

4.34 (d, J = 13.1 Hz, 2 H, H_axof ArCH₂Ar), 4.30 (d, J = 12.9 Hz,

2 H, H_axof ArCH₂Ar), 4.05–3.89 (m, 4 H, OCH₂CH₂), 3.51 (d, J

= 13.1 Hz, 2 H, H_eqof ArCH₂Ar), 3.37 (d, J = 12.9 Hz, 2 H, H_eq

of ArCH₂Ar), 2.34 (q, J = 7.5 Hz, 2 H, COCH₂), 2.16–2.02 (m, 4

H, OCH₂CH₂), 1.33 (t, J = 7.4 Hz, 6 H, CH₂CH₂CH₃), 1.24 (t, J

= 7.7 Hz, 3 H, COCH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 171.6 and 162.6 (CO), 160.6, 151.7, 150.0, 143.5, 133.3, 131.9,

131.7, 129.5, 129.4, 129.1, 129.0, 128.9, 128.5, 128.0, 125.5, 124.6,

120.5, 120.4, 114.4, 108.6, 78.5 (OCH₂CH₂), 31.3 and 30.5 (Ar-

CH₂Ar), 23.4 (OCH₂CH₂), 14.1 (COCH₂), 10.8 (OCH₂CH₂CH₃),

9.6 (COCH₂CH₃) ppm. ESI-MS: m/z (%) = 763.8 (100) [M +

Na]⁺. C₄₄H₄₄N₄O₇(740.32): calcd. C 71.33, H 5.99, N 7.56; found

C 71.40, H 6.03, N 7.50.

General Procedure for the Synthesis of Peptidocalixarenes 12–18, 20

and 21: The appropriate C-protected amino acid or dipeptide or

n-butylamine (0.13 mmol), NEt₃(0.14 mL, 1.0 mmol) and HBTU

(92 mg, 0.24 mmol) were added to a solution of intermediate 6–9

or 11 (0.07 mmol) in dry CH₂Cl₂(5 mL). The reaction was stirred

at room temp. for 5–10 h and then was quenched by adding dis-

tilled water (10 mL). The organic layer was diluted to 20 mL, sepa-

rated and the solvents evaporated to dryness under reduced pres-

sure.

11-(N-Cbz-L-Alanyl-L-alanyl)amino-23-benzotriazolyloxycarbonyl-

25,27-dihydroxy-26,28-dipropoxycalix[4]arene (8): The crude was

purified by flash column chromatography (eluent: CH₂Cl₂/MeOH,

20:1) to obtain the product as a white solid. Yield 59 mg,

1

0.06 mmol, 34%. M.p. 181–183 °C. H NMR (300 MHz, CDCl₃):

δ = 9.53 (s, 1 H, OH), 8.01 (s, 1 H, NH), 8.19 (s, 1 H, OH), 8.10–

8.00 (m, 3 H, ArH), 7.53–7.42 (m, 2 H, ArH), 7.42–7.16 (m, 8 H,

ArH), 7.06–6.83 (m, 5 H, 4 ArH and NH), 6.75–6.58 (m, 2 H,

ArH), 5.68–5.55 (br. s, 1 H, NH), 5.13 (d, J = 15.0 Hz, 1 H, CH₂

Cbz), 5.05 (d, J = 15.0 Hz, 1 H, CH₂Cbz), 4.68–4.55 (m, 1 H,

CH), 4.41–4.17 (m, 5 H, CH and H_axof ArCH₂Ar), 4.05–3.84 (m,

4 H, OCH₂), 3.49 (d, J = 17.5 Hz, 2 H, H_eqof ArCH₂Ar), 3.34 (d,

J = 12.9 Hz, 2 H, H_eqof ArCH₂Ar), 2.14–1.95 (m, 4 H,

OCH₂CH₂), 1.45–1.20 (m, 12 H, CHCH₃and CH₂CH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 172.6, 169.7, 162.6 and 160.6 (CO),

151.7, 150.1, 143.5, 135.9, 133.3, 131.9, 131.7, 129.4, 129.4, 129.2,

129.0, 128.9, 128.5, 128.2, 128.1, 128.0, 125.5, 124.7, 120.6, 120.4,

114.4 and 108.6 (Ar), 78.5 (OCH₂CH₂), 67.2 (CH₂), 51.1 and 49.5

(CH), 31.3 (ArCH₂Ar), 23.4 (OCH₂CH₂), 18.6 and 17.9 (CH₃),

10.8 (OCH₂CH₂CH₃) ppm. ESI-MS: m/z (%) = 983.6 (88) [M +

Na]⁺. C₅₅H₅₆N₆O₁₀(960.40): calcd. C 68.73, H 5.87, N 8.74; found

C 68.80, H 5.84, N 8.81.

11-(N-Cbz-L-Alanyl)amino-25,27-dihydroxy-23-(methoxy-L-alanyl)-

carbonyl-26,28-dipropoxycalix[4]arene (12): The crude was purified

by flash column chromatography (eluent: hexane/AcOEt, 1:1, v/v)

to give the product as a white solid. Yield 52 mg, 0.06 mmol, 90%.

M.p. 241.2–243.5 °C. [α]²_D⁰= –4.0 (c = 0.76, in CHCl₃). H NMR

1

(300 MHz, CDCl₃, c = 10^–2): δ = 8.93 (br. s, 1 H, ArNH), 8.89

(s, 1 H, OH), 8.04 (s, 1 H, OH), 7.56 (s, 2 H, ArH), 7.32 (br. s, 7

H, ArH) 6.75 (d, J = 7.1 Hz, 1 H, ArCONH), 6.31 (br. s, 4 H,

ArH), 5.80 (br. s, 2 H, ArH), 5.60 (br. s, 1 H, NHCbz), 5.04–5.18

(m, 2 H, CH₂Ph), 4.91–4.78 (m, 1 H, CHCOOCH₃), 4.40–4.56 (m,

1 H, CHNHCbz), 4.22 (d, J = 12.3 Hz, 2 H, H_axof ArCH₂Ar),

4.20 (d, J = 12.9 Hz, 2 H, H_axof ArCH₂Ar), 3.90 (t, J = 5.6 Hz, 4

H, OCH₂CH₂), 3.79 (s, 3 H, OCH₃), 3.32 (d, J = 12.9 Hz, 1 H,

H_eqof ArCH₂Ar), 3.31 (d, J = 12.9 Hz, 1 H, H_eqof ArCH₂Ar),

3.24 (d, J = 12.9 Hz, 1 H, H_eqof ArCH₂Ar), 3.22 (d, J = 12.9 Hz,

1 H, H_eqof ArCH₂Ar), 2.11–1.95 (m, 4 H, OCH₂CH₂), 1.55 [d, J

= 6.9 Hz, 3 H, CH(CH₃)COOCH₃], 1.50 [d, J = 7.2 Hz, 3 H,

CH(CH₃)NHCbz], 1.29 (t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 173.9, 170.6, 167.3 and 157.8 (CO),

151.4, 150.0, 136.4, 131.8, 131.0, 129.6, 129.1, 128.8, 128.4, 128.3,

128.1, 127.9, 127.8, 127.7, 125.1, 122.6 and 120.0 (Ar), 77.9

23-Benzotriazolyloxycarbonyl-25,27-dihydroxy-11-(N-Cbz-

L-leucyl-

L-isoleucyl)amino-26,28-dipropoxycalix[4]arene (9): The crude was

purified by flash column chromatography (eluent: CH₂Cl₂/MeOH,

95:5) to obtain the product as a white solid. Yield 96 mg,

1

0.09 mmol, 51%. H NMR (300 MHz, CDCl₃): δ = 9.55 (s, 1 H,

OH), 8.24 (s, 1 H, OH), 8.08 (d, J = 8.2 Hz, 1 H, ArH), 8.02 (s, 2

H, ArH), 7.57–7.38 (m, 3 H, ArH), 7.35–7.24 (m, 8 H, ArH and (OCH₂CH₂), 66.8 (CH₂Ph), 52.5 (OCH₃), 48.7 and 51.6 (CHCH₃),

NH), 6.96 (br. s, 4 H, ArH), 6.73 (t, J = 7.3 Hz, 2 H, ArH), 6.60

(br. s, 1 H, NHCbz), 5.10 (br. s, 2 H, CH₂Ph), 4.70–4.52 (m, 2 H,

31.9, 31.7, 31.6 and 31.4 (ArCH₂Ar), 23.4 (OCH₂CH₂), 18.9 and

18.5 (CHCH₃), 10.7 (CH₂CH₃) ppm. ESI-MS: m/z (%) = 880.2

2 CH), 4.32 (d, J = 13.2 Hz, 2 H, H_axof ArCH₂Ar), 4.28 (d, J = (100) [M + Na]⁺. C₅₀H₅₅N₃O₁₀(857.39): calcd. C 69.99, H 6.46, N

12.9 Hz, 2 H, H_axof ArCH₂Ar), 3.99 (br. s, 4 H, OCH₂CH₂), 3.51

4.90; found C 70.14, H 6.51, N 4.79.

880

www.eurjoc.org

Eur. J. Org. Chem. 2008, 869–886

Chiral Dimeric Capsules from Peptidocalix[4]arenes

11-(N-Cbz- -Alanyl)amino-25,27-dihydroxy-23-(methoxy-

L

D

-alanyl)- [2M + 2Na + Cl]⁺. C₄₆H₅₅N₃O₉(793.39): calcd. C 69.59, H 6.98,

N 5.29; found C 69.67, H 7.09, N 5.25.

carbonyl-26,28-dipropoxycalix[4]arene (13): The crude was purified

by flash column chromatography (eluent: CH₂Cl₂/MeOH, 40:1,

v/v) to give the product as a white solid. Yield 46 mg, 0.05 mmol,

11-(N-Cbz- -Alanyl- -alanyl)amino-25,27-dihydroxy-23-(methoxy-

L

L-alanyl)carbonyl-26,28-dipropoxycalix[4]arene (16): The crude was

1

76%. M.p. 233–236 °C. H NMR (300 MHz, CDCl₃, c = 10^–2):

purified by flash column chromatography (eluent: CH₂Cl₂/MeOH,

30:1, v/v) to give the product as a white solid. Yield 30 mg,

0.03 mmol, 46%. ¹H NMR (300 MHz, CDCl₃, c = 10^–2): δ =

8.95 (br. s, 1 H, ArNH), 8.92 (s, 1 H, OH), 8.09 (s, 1 H, OH), 7.56

(s, 2 H, ArH), 7.41–7.28 (m, 7 H, ArH), 6.79 (br. s, 1 H, NH), 6.76

(br. s, 1 H, NH), 6.52 (br. s, 5 H, ArH and NH), 5.92 (br. s, 2 H,

ArH), 5.35 (br. s, 1 H, CH), 5.11 (br. s, 2 H, CH₂Ph), 4.82 (quint.,

J = 6.9 Hz, 1 H, CH), 4.67 (quint., J = 6.6 Hz, 1 H, CH), 4.26–

4.19 (m, 1 H, 4 H, H_axof ArCH₂Ar), 3.91 (br. s, 4 H, OCH₂CH₂),

3.79 (s, 3 H, OCH₃), 3.37–3.22 (m, 4 H, H_eqof ArCH₂Ar), 2.05–

1.98 (m, 4 H, OCH₂CH₂), 1.56 (d, J = 6.9 Hz, 3 H, CH₃), 1.47 (d,

J = 6.6 Hz, 3 H, CH₃), 1.39 (d, J = 5.7 Hz, 3 H, CH₃), 1.27 (t, J

= 7.2 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

173.9, 169.7, 167.0, 157.4 and 155.5 (CO), 151.5, 150.1, 132.4,

131.5, 129.3, 129.1, 128.8, 128.4, 128.2, 128.1, 127.9, 125.2, 120.3

and 120.2 (Ar), 78.1 (OCH₂CH₂), 67.1 (CH₂Ph), 52.5 (OCH₃),

50.8, 49.6 and 48.5 (CHCH₃), 31.5 (ArCH₂Ar), 23.4 (OCH₂CH₂),

18.5 and 18.3 (CHCH₃), 10.7 (OCH₂CH₂CH₃) ppm. ESI-MS: m/z

(%) = 951.6 (100) [M + Na]⁺, 1880.2 (10) [2M + Na]⁺.

C₅₃H₆₀N₄O₁₁(928.42): calcd. C 68.52, H 6.51, N 6.03; found C

68.50, H 6.59, N 6.14.

δ = 9.06 (br. s, 1 H, NH), 8.91 (s, 1 H, OH), 8.04 (s, 1 H, OH),

7.57 (s, 1 H, ArH), 7.55 (s, 1 H, ArH), 7.35–7.31 [m, 7 H, 2 ArH

and 5 ArH(Cbz)], 6.75 (d, J = 7.2 Hz, 1 H, NH), 6.26 (br. s, 4 H,

ArH), 5.71 (br. s, 1 H, NH), 5.66 (br. s, 2 H, ArH), 5.15–5.04 (m,

2 H, CH₂Cbz), 4.83 [quint., J = 7.2 Hz, 1 H, CH(AlaOMe)], 4.49–

4.45 [m, 1 H, CH(CbzAla)], 4.22–4.16 (m, 4 H, H_axof ArCH₂Ar),

3.89 (br. s, 4 H, OCH₂CH₂), 3.79 (s, 3 H, OCH₃), 3.31 (d, J =

13.3 Hz, 1 H, H_eqof ArCH₂Ar), 3.30 (d, J = 13.3 Hz, 1 H, H_eqof

ArCH₂Ar), 3.23 (d, J = 13.0 Hz, 1 H, H_eqof ArCH₂Ar), 3.21 (d,

J = 12.9 Hz, 1 H, H_eqof ArCH₂Ar), 2.07–1.95 (m, 4 H,

OCH₂CH₂), 1.56–1.44 [m, 6 H, CHCH₃(AlaOMe) and CHCH₃

(CbzAla)], 1.26–1.25 (m, 6 H, CH₂CH₃) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 173.9, 170.5, 167.3 and 157.9 (CO), 151.4, 150.0,

136.4, 131.9, 130.9, 129.7, 129.0, 128.8, 128.3, 128.1, 128.0, 127.9,

127.8, 127.7, 125.1, 122.6 and 119.9 (Ar), 77.9 (OCH₂CH₂), 66.7

(CH₂Cbz), 52.5 (OCH₃), 51.5 and 48.6 (CH), 31.6 and 31.5 (Ar-

CH₂Ar), 23.3 (OCH₂CH₂), 19.1 and 18.5 (CH₃), 10.7

(OCH₂CH₂CH₃) ppm. ESI-MS: m/z (%) = 880.5 (77) [M + Na]⁺.

C₅₀H₅₅N₃O₁₀(857.39): calcd. C 69.99, H 6.46, N 4.90; found C

70.10, H 6.40, N 4.80.

11-(N-Cbz-L-Alanyl)amino-25,27-dihydroxy-23-(methoxy-L-phenyl-

11-(N-Cbz-

L-alanyl-L-Alanyl)amino-25,27-dihydroxy-23-(methoxy-

alanyl)carbonyl-26,28-dipropoxycalix[4]arene (14): The crude was

purified by flash column chromatography (eluent: CH₂Cl₂/MeOH,

40:1, v/v) to give the product as a white solid. Yield 47 mg,

0.05 mmol, 76 %. M.p. 217.5–220.0 °C. ¹H NMR (300 MHz,

CDCl₃, c = 10^–2): δ = 8.93 (s, 1 H, OH), 8.81 (br. s, 1 H, NH),

8.08 (s, 1 H, OH), 7.48 (s, 1 H, ArH), 7.46 (s, 1 H, ArH), 7.35–

7.26 [m, 7 H, 5 Ar(Cbz) and 2 ArH], 7.16 (s, 1 H, ArH), 7.14 (s, 1

H, ArH), 6.57 (d, J = 7.5 Hz, 1 H, NH), 6.39 (br. s, 4 H, ArH),

5.91 (br. s, 1 H, NH), 5.55 (br. s, 2 H, ArH), 5.16–5.07 [m, 3 H,

CH₂(Cbz) and CH(Phe)], 4.45 (m, 1 H, CHCH₃), 4.21 (d, J =

13.0 Hz, 4 H, H_axof ArCH₂Ar), 3.90 (br. s, 4 H, OCH₂CH₂), 3.77

(s, 3 H, OCH₃), 3.33–3.22 (m, 6 H, H_eqof ArCH₂Ar and CHCH₂),

2.05–1.98 (m, 4 H, OCH₂CH₂), 1.49 (d, J = 6.0 Hz, 3 H, CHCH₃),

1.24 (t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 172.3, 170.4, 167.1 and 157.7 (CO), 151.4, 150.1,

136.3, 135.9, 132.1, 131.1, 129.5, 129.3, 129.2, 129.1, 128.7, 128.6,

128.5, 128.4, 128.3, 128.1, 127.9, 127.7, 127.1, 125.1, 122.7 and

120.1 (Ar), 78.0 (OCH₂CH₂), 66.8 (CH₂Cbz), 53.6 (OCH₃), 52.3

and 51.4 (CH), 37.9 (CH₂), 31.6, 31.5 and 31.4 (ArCH₂Ar), 23.4

(OCH₂CH₂), 18.9 (CH₃), 10.7 (OCH₂CH₂CH₃) ppm. ESI-MS: m/z

(%) = 956.6 (48) [M + Na]⁺. C₅₆H₅₉N₃O₁₀(934.10): calcd. C 72.01,

H 6.37, N 4.50; found C 72.15, H 6.28, N 4.64.

L

-alanyl- -alanyl)carbonyl-26,28-dipropoxycalix[4]arene (17): The

L

crude was purified by flash column chromatography (eluent:

CH₂Cl₂/MeOH, 20:1.5, v/v) to give the product as a white solid.

Yield 26 mg, 0.03 mmol, 37%. M.p. 165.2–168.6 °C. [α]²_D⁰= –13.0

(c = 0.54, in CHCl₃). ¹H NMR (300 MHz, CDCl₃, c = 4ϫ10^–2):

δ = 9.74 (br. s, 1 H, ArNH), 8.98 (s, 1 H, OH), 8.02 (s, 1 H, OH),

7.67–7.48 (m, 3 H, ArH and NH), 7.32 (br. s, 9 H, ArH and NH),

5.82 (br. s, 6 H, ArH), 5.73 (d, J = 7.6 Hz, 1 H, NHCbz), 5.20–

5.06 (m, 2 H, CH₂Ph), 5.06–4.95 (m, 1 H, ArCONHCH), 5.00–

4.85 (m, 1 H, ArNHCOCH), 4.61–4.49 (m, 1 H, CHCOOCH₃),

4.48–4.36 (m, 1 H, CHNHCbz), 4.25–4.01 (m, 4 H, H_axof Ar-

CH₂Ar), 3.83 (br. s, 4 H, OCH₂CH₂), 3.72 (s, 3 H, OCH₃), 3.36–

3.03 (m, 4 H, H_eqof ArCH₂Ar), 2.08–1.80 (m, 4 H, OCH₂CH₂),

1.60 (d, J = 6.9 Hz, 3 H, ArCONHCHCH₃), 1.53 (d, J = 6.8 Hz,

3 H, ArNHCOCHCH₃), 1.43 [d, J = 6.5 Hz, 3 H, CH(CH₃)-

NHCbz], 1.33 [d, J = 7.1 Hz, 3 H, CH(CH₃)COOCH₃], 1.23 (t, J

= 7.2 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

173.1, 172.5, 171.8, 170.4 and 167. 6 (CO), 158.1 (Ar), 156.0 (CO),

151.5, 151.3, 150.4, 136.1, 131.7, 131.4, 130.5, 129.3, 129.1, 128.9,

128.8, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,

125.2, 125.1, 122.3, 120.4 and 120.2 (Ar), 77.9 (OCH₂CH₂), 67.0

(CH₂Ph), 52.4 (COOCH₃), 50.0, 49.9, 49.4 and 49.2 (CHCH₃), 31.7

and 31.6 (ArCH₂Ar), 23.4 (OCH₂CH₂), 19.4, 18.9, 17.8 and 17.7

(CHCH₃), 10.8 (OCH₂CH₂CH₃) ppm. ESI-MS: m/z (%) = 1022.8

(100) [M + Na]⁺. C₅₆H₆₅N₅O₁₂(999.46): calcd. C 67.25, H 6.55, N

7.00; found C 67.32, H 6.51, N 6.89.

11-[N-Acetyl-(dl)-leucyl]amino-25,27-dihydroxy-23-(methoxy-L-gly-

cyl)carbonyl-26,28-dipropoxycalix[4]arene (15): The crude was puri-

fied by flash column chromatography (eluent: CH₂Cl₂/AcOEt, 1:1,

v/v) to give the product as a white solid. Yield 18 mg, 0.02 mmol,

1

31%. H NMR (300 MHz, CDCl₃, c = 10^–2): δ = 8.92 (s, 1 H,

OH), 8.82 (s, 1 H, NH), 8.12 (s, 1 H, OH), 7.57 (s, 2 H, ArH), 7.31

25,27-Dihydroxy-11-(N-Cbz-

L-leucyl-L-isoleucyl)amino-23-(meth-

(s, 2 H, ArH), 6.75 (t, J = 3.9 Hz, 1 H, NH), 6.50 (br. s, 4 H, ArH),

oxy- -phenylalanyl- -valyl)carbonyl-26,28-dipropoxycalix[4]arene

L

6.18 (d, J = 9.0 Hz, 1 H, NH), 6.04 (br. s, 2 H, ArH), 4.64 (q, J = (18): The crude was purified by flash column chromatography (elu-

8.1 Hz, 1 H, CH), 4.27–4.18 (m, 6 H, CH₂and H_axof ArCH₂Ar), ent: CH₂Cl₂/MeOH, 98:2, v/v) to give the product as a white solid.

3.90 (br. s, 4 H, OCH₂CH₂), 3.79 (s, 3 H, CH₃), 3.35 (d, J =

12.9 Hz, 1 H, H_eqof ArCH₂Ar), 3.33 (d, J = 13.5 Hz, 1 H, H_eqof MeOD, 8:2): δ = 7.75 (s, 1 H, ArH), 7.74 (s, 1 H, ArH), 7.41–7.26

Yield 27 mg, 0.02 mmol, 32%. ¹H NMR (300 MHz, [D₆]acetone/

ArCH₂Ar), 3.25 (d, J = 13.2 Hz, 2 H, H_eqof ArCH₂Ar), 2.05–1.98

(m, 4 H, OCH₂CH₂), 1.98 (s, 3 H, COCH₃), 1.82–1.71 (m, 3 H,

(m, 10 H, ArH), 7.18 (s, 1 H, ArH), 7.17 (s, 1 H, ArH), 6.94 (d, J

= 7.2 Hz, 2 H, ArH), 6.89 (d, J = 7.2 Hz, 2 H, ArH), 6.56 (t, J =

CH and CH₂), 1.23 (t, J = 7.3 Hz, 6 H, CH₂CH₃), 0.91 (br. s, 6 H, 7.2 Hz, 2 H, ArH), 5.09 (br. s, 2 H, CH₂Cbz), 4.67 (t, J = 6.3 Hz,

CH₃) ppm. ESI-MS: m/z (%) = 816.4 (100) [M + Na]⁺, 1668 (10)

1 H, CH), 4.44 (t, J = 7.5 Hz, 1 H, CH), 4.38–4.24 (m, 6 H, 2 CH

Eur. J. Org. Chem. 2008, 869–886

www.eurjoc.org

881

L. Baldini, R. Ungaro et al.

and H_axof ArCH₂Ar), 4.00 (t, J = 6.0 Hz, 4 H,OCH₂CH₂), 3.62 tripeptide Cbz-NH--Ala--Ala--Ala (154 mg, 0.42 mmol) in a

FULL PAPER

(s, 3 H, OCH₃), 3.50 (d, J = 12.9 Hz, 2 H, H_eqof ArCH₂Ar), 3.36

(d, J = 12.6 Hz, 2 H, H_eqof ArCH₂Ar), 3.10 (dd, J = 11.1, 6.0 Hz,

1 H, CHHPh), 2.99 (dd, J = 11.1, 8.1 Hz, 1 H, CHHPh), 2.13–2.08

mixture of dry CH₂Cl₂and dry DMF (20 mL, 3:1, v/v). The mix-

ture was stirred for 72 h at room temp. The solvents were removed

in vacuo and the residue was dissolved in CH₂Cl₂(20 mL). The

(m, 5 H, OCH₂CH₂and CH), 1.90 (br. s, 1 H, CH), 1.75–1.68 (m, organic layer was washed with 0.01  HCl (15 mL) and H₂O

1 H, CH), 1.57 (t, J = 7.5 Hz, 2 H, CH₂), 1.34 (t, J = 7.5 Hz, 6 H, (15 mL) and the solvent evaporated to dryness. The crude was puri-

CH₂CH₃), 1.20–1.08 (m, 2 H, CH₂), 0.95–0.83 (m, 18 H, CH₃). fied by flash chromatography (gradient from CH₂Cl₂to CH₂Cl₂/

ESI-MS: m/z (%) = 1211.1 (100) [M + Na]⁺. C₇₀H₈₅N₅O₁₂

(1187.62): calcd. C 70.74, H 7.21, N 5.89; found C 70.82, H 7.15,

N 5.78.

MeOH, 9:1, v/v) to obtain intermediate 10. Compound 10 (53 mg,

0.05 mmol) was dissolved in a mixture of dry CH₂Cl₂and dry

DMF (15 mL, 3:1, v/v) and the tripeptide -Ala--Ala--AlaOMe

(55 mg, 0.15 mmol), NEt₃(150 µL, 1.1 mmol) and HBTU (150 mg,

0.40 mmol) were added to this solution. The mixture was stirred

for 48 h at room temp. The solvents were removed in vacuo and

the residue was dissolved in CH₂Cl₂(15 mL). The organic layer

was washed with 0.01  HCl (10 mL) and H₂O (10 mL) and the

solvents evaporated to dryness. After flash chromatography (gradi-

ent from CH₂Cl₂/MeOH, 20:1, v/v to CH₂Cl₂/MeOH, 15:1, v/v)

pure 19 was obtained as a white solid. Yield 34 mg, 0.03 mmol,

23-Butylaminocarbonyl-25,27-dihydroxy-11-propanoylamino-26,28-

dipropoxycalix[4]arene (20): The crude was purified by flash column

chromatography (eluent: CH₂Cl₂/MeOH, 40:1, v/v) to give the

product as a white solid. Yield 21 mg, 0.03 mmol, 45 %. M.p.

1

Ͼ300 °C. H NMR (300 MHz, CDCl₃, c = 10^–2): δ = 8.84 (s, 1

H, OH), 8.19 (br. s, 1 H, ArNH), 8.01 (s, 1 H, OH), 7.52 (s, 2 H,

ArH), 7.32 (s, 2 H, ArH), 6.43 (br. s, 4 H, ArH), 6.09 (br. s, 1 H,

NHCH₂), 5.96 (br. s, 2 H, ArH), 4.24 (d, J = 13.2 Hz, 2 H, H_axof

ArCH₂Ar), 4.22 (d, J = 13.2 Hz, 2 H, H_axof ArCH₂Ar), 3.91 (br.

s, 4 H, OCH₂), 3.53–3.42 (m, 2 H, NHCH₂), 3.33 (d, J = 13.2 Hz,

2 H, H_eqof ArCH₂Ar), 3.25 (d, J = 13.2 Hz, 2 H, H_eqof Ar-

CH₂Ar), 2.44 (q, J = 3.7 Hz, 2 H, COCH₂), 2.09–1.96 (m, 4 H,

OCH₂CH₂), 1.68–1.51 (m, 2 H, NHCH₂CH₂), 1.49–1.36 (m, 2 H,

NHCH₂CH₂CH₂), 1.35–1.19 (m, 9 H, OCH₂CH₂CH₃and

NHCOCH₂CH₃), 0.96 (t, J = 8.0 Hz, 3 H, CONHCH₂-

CH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 167.6 and

156.9 (CO), 151.7, 149.9, 132.8, 132.1, 129.8, 129.2, 128.9, 128.2,

128.0, 127.6, 125.3 and 124.7 (Ar), 78.2 (OCH₂CH₂), 39.8

(NHCH₂), 32.0 and 31.5 (ArCH₂Ar), 29.7 (NHCH₂CH₂), 23.5

(OCH₂CH₂), 20.2 (NHCH₂CH₂CH₂), 15.4 (COCH₂), 13.8

( N H C H ₂C H ₂C H ₂C H ₃) , 1 0 . 8 ( O C H ₂C H ₂C H ₃) , 9 . 8

(COCH₂CH₃) ppm. ESI-MS: m/z (%) = 701.6 (100) [M + Na]⁺.

C₄₂H₅₀N₂O₆(678.36): calcd. C 74.31, H 7.42, N 4.13; found C

74.37, H 7.38, N 4.05.

1

14%. H NMR (300 MHz, CDCl₃, c = 10^–2): δ = 9.28 (br. s, 1

H, NH), 8.95 (s, 1 H, OH), 8.06 (s, 1 H, OH), 7.73 (br. s, 1 H,

NH), 7.58 (s, 2 H, ArH), 7.39 (br. s, 1 H, NH), 7.27 (br. s, 8 H,

ArH and NH), 6.85 (br. s, 2 H, NH), 6.17 (br. s, 6 H, ArH), 5.82

(br. s, 1 H, NH), 5.07 (m, 2 H, CH₂Ph), 4.91 (br. s, 1 H, CH), 4.77

(br. s, 1 H, CH), 4.54–4.50 (m, 2 H, CH), 4.25 (br. s, 1 H, CH),

4.19–4.15 (m, 4 H, H_{a x}of ArCH₂Ar), 3.86 (br. s, 4 H,

OCH₂CH₂CH₃), 3.67 (s, 3 H, OCH₃), 3.31–3.17 (m, 4 H, H_eqof

ArCH₂Ar), 1.99 (br. s, 4 H, OCH₂CH₂CH₃), 1.71 (br. s, 6 H, CH₃),

1.50 (br. s, 6 H, CH₃), 1.35 (br. s, 6 H, CH₃), 1.24 (br. s, 6 H,

OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 173.2,

172.8, 172.7, 171.8, 170.5, 167.6, 157.8, 156.2, 151.6, 150.3, 136.1,

133.9, 132.1, 131.2, 129.4, 129.1, 128.9, 128.8, 128.5, 128.4, 128.2,

128.0, 125.2, 120.5, 78.1, 67.1, 52.4, 51.1, 49.9, 49.5, 49.1, 48.1,

31.6, 29.7, 23.4, 19.2, 18.7, 18.5, 18.2, 18.0, 10.8 ppm. MS (ESI-

MS): calcd. for C₆₂H₇₅N₇O₁₄1141.5; found 1164.6 (100, [M +

Na]⁺), 2306.1 (5, [2M + Na]⁺). C₆₂H₇₅N₇O₁₄(1141.53): calcd. C

65.19, H 6.62, N 8.58; found C 65.22, H 6.57, N 8.49.

11-(N-Cbz-L-Alanyl)amino-23-butylaminocarbonyl-25,27-di-

hydroxy-26,28-dipropoxycalix[4]arene (21): The crude was purified

by flash column chromatography (eluent: CH₂Cl₂/MeOH, 35:1,

v/v) to give the product as a white solid. Yield 55 mg, 0.06 mmol,

94 %. M.p. 195 °C (decomp.).¹H NMR (300 MHz, CDCl₃, c =

10^–2): δ = 9.31 (br. s, 1 H, NH), 8.90 (s, 1 H, OH), 8.05 (s, 1 H,

OH), 7.53 (s, 2 H, Ar), 7.37–7.34 (m, 7 H, ArH), 6.17 (br. s, 5 H,

NH and ArH), 5.77 (br. s, 1 H, NH Cbz), 5.62 (br. s, 2 H, ArH),

5.11 (m, 2 H, CH₂Cbz), 4.55 (br. s, 1 H, CH), 4.25–4.18 (m, 4 H,

H_axof ArCH₂Ar), 3.90 (br. s, 4 H, OCH₂CH₂), 3.51 (br. s, 2 H,

NHCH₂), 3.31 (d, J = 13.3 Hz, 1 H, H_eqof ArCH₂Ar), 3.30 (d, J

= 13.4 Hz, 1 H, H_eqof ArCH₂Ar), 3.23 (d, J = 13.1 Hz, 2 H, H_eq

of ArCH₂Ar), 2.08–1.99 (m, 4 H,OCH₂CH₂), 1.75–1.55 (m, 2 H,

NHCH₂CH₂), 1.53 (d, J = 6.8 Hz, 3 H, CHCH₃), 1.48–1.32 (m, 2

H, NHCH₂CH₂CH₂), 1.25 (t, J = 7.8 Hz, 6 H, OCH₂CH₂CH₃),

0.97 (t, J = 7.3 Hz, 3 H, NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 170.5, 167.8 and 157.3 (CO), 151.5, 150.0,

136.4, 132.2, 131.4, 129.6, 129.1, 128.8, 128.5, 128.2, 128.0, 127.0,

125.2, 123.8 and 120.1 (Ar), 78.1 (OCH₂CH₂), 66.9 (CH₂Cbz),

51.5 (CH), 39.9 (NHCH₂), 31.9, 31.7 and 31.5 (ArCH₂Ar), 29.7

(NHCH₂CH₂), 23.5 (OCH₂CH₂), 20.2 (NHCH₂CH₂CH₂), 19.0

(CH₃), 13.9 (NHCH₂CH₂CH₂CH₃), 10.9 (OCH₂CH₂CH₃) ppm.

ESI-MS: m/z (%) = 850.7 (100) [M + Na]⁺. C₅₀H₅₇N₃O₈(827.41):

calcd. C 72.53, H 6.94, N 5.07; found C 72.65, H 7.02, N 4.95.

5-Nitro-25,26,27,28-tetrapropoxycalix[4]arene-17-carbaldehyde (25):

A solution of 65% HNO₃(0.3 mL) was added to a solution of 5-

formyl-25,26,27,28-tetrapropoxycalix[4]arene (24)^[21](450 mg,

0.72 mmol) in CH₂Cl₂(10 mL) and acetic acid (1.0 mL). The reac-

tion mixture was stirred for 3 h at room temp., quenched by ad-

dition of a NaHCO₃saturated solution (10 mL) and vigorously

stirred for 10 min. The organic layer was separated, washed with

distilled water (2ϫ10 mL), dried with Na₂SO₄and the solvents

evaporated to dryness at reduced pressure. The crude was purified

by flash chromatography (eluent: hexane/ethyl acetate, 93:7, v/v) to

obtain the product as a pale yellow solid. Yield 185 mg, 0.28 mmol,

1

39%. M.p. 121–122 °C. H NMR (300 MHz, CDCl₃): δ = 9.47 (s,

1 H, CHO), 7.29 (s, 2 H, ArH), 6.98 (s, 2 H, ArH), 6.89–6.75 (m,

6 H, ArH), 4.47 (d, J = 13.8 Hz, 4 H, H_axof ArCH₂Ar), 3.97–3.85

(m, 8 H, OCH₂CH₂CH₃), 3.24 (d, J = 13.8 Hz, 2 H, H_eqof Ar-

CH₂Ar), 3.22 (d, J = 13.8 Hz, 2 H, H_eqof ArCH₂Ar), 2.00–1.87

(m, 8 H, OCH₂CH₂CH₃), 1.05 (t, J = 7.5 Hz, 3 H, OCH₂CH₂CH₃),

1.04 (t, J = 7.5 Hz, 3 H, OCH₂CH₂CH₃), 0.96 (t, J = 7.5 Hz, 3 H,

OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 190.7,

161.7, 156.5, 142.3, 136.1, 135.6, 135.0, 134.3, 129.6, 129.1, 128.7,

123.2, 122.8, 77.1, 76.9, 76.7, 31.0, 30.9, 23.3, 23.0, 10.3, 10.0 ppm.

MS (ESI-MS): calcd. for C₄₁H₄₇NO₇665.3; found 688.7 [M +

Na]⁺. C₄₁H₄₇NO₇(665.33): calcd. C 73.96, H 7.12, N 2.10; found

C 74.05, H 7.20, N 2.03.

11-(N-Cbz-

L

-Alanyl-

L

-alanyl-

L-alanyl)amino-25,27-dihydroxy-23-

(methoxy- -alanyl-

[4]arene (19): NEt₃(250 µL, 1.8 mmol) and HBTU (490 mg,

1.3 mmol) were added to a solution of 5 (120 mg, 0.21 mmol) and

L

-alanyl-

L

-alanyl)carbonyl-26,28-dipropoxycalix-

Alternative Procedure for the Synthesis of 25: SnCl₄(0.17 mL,

1.41 mmol) was added to a solution of 5-nitro-25,26,27,28-tetra-

propoxycalix[4]arene (23)^[20](300 mg, 0.47 mmol) and α,α-dichlo-

882

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Eur. J. Org. Chem. 2008, 869–886

Chiral Dimeric Capsules from Peptidocalix[4]arenes

romethyl methyl ether (0.13 mL, 1.41 mmol) in dry CHCl₃(20 mL)

cooled to –12 °C with an ice/salt bath. The reaction mixture was

stirred without making any addition to the cold bath, thus letting

the temperature slowly increase. After 1.5 h the reaction was

quenched by the addition of 1  HCl (50 mL). The organic phase

was washed with H₂O (2ϫ30 mL), dried with Na₂SO₄and the sol-

vents evaporated to dryness under reduced pressure. Pure 25 was

obtained after recrystallization from CH₂Cl₂/hexane (1:1, v/v).

Yield 45 mg, 0.07 mmol, 14%.

(d, J = 14.5 Hz, 2 H, H_axof ArCH₂Ar), 3.82 (t, J = 8.4 Hz, 4 H,

OCH₂CH₂CH₃), 3.69 (t, J = 6.4 Hz, 2 H, OCH₂CH₂CH₃), 3.68 (t,

J = 6.5 Hz, 2 H, OCH₂CH₂CH₃), 3.17 (d, J = 14.4 Hz, 2 H, H_eq

of ArCH₂Ar), 3.15 (d, J = 14.5 Hz, 2 H, H_eqof ArCH₂Ar), 1.83–

1.69 (m, 8 H, OCH₂CH₂CH₃), 1.10 (t, J = 7.3 Hz, 3 H,

OCH₂CH₂CH₃), 1.09 (t, J = 7.3 Hz, 3 H, OCH₂CH₂CH₃), 0.82 (t,

J = 7.5 Hz, 6 H, OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 175.2, 158.9, 155.4, 155.0, 137.8, 137.4, 135.3, 134.6,

131.1, 129.8, 129.7, 129.5, 129.4, 125.2, 121.8, 76.2, 76.1, 76.0, 31.2,

23.4, 23.3, 23.0, 10.8, 9.7 ppm. MS (ESI-MS): calcd. for

C₄₁H₄₇NO₅633.3; found 656.6 [M + Na]⁺. C₄₁H₄₇NO₅(633.34):

calcd. C 77.69, H 7.47, N 2.21; found C 77.75, H 7.40, N 2.28.

5-Nitro-25,26,27,28-tetrapropoxycalix[4]arene-17-carboxylic Acid

(26): A solution of 25 (165 mg, 0.25 mmol) in CHCl₃/acetone

(10 mL, 1:1, v/v) was cooled to 0 °C and treated with an aqueous

solution (1.5 mL) of H₂NSO₃H (80 mg, 0.82 mmol) and NaClO₂5-(Boc-Amino)-25,26,27,28-tetrapropoxycalix[4]arene-17-carboxylic

(49 mg, 0.54 mmol). The mixture was vigorously stirred at room

temp. for 4 h. Then the organic solvents were evaporated under

reduced pressure and 1  HCl (5 mL) was added to give 26 as a pale

Acid (30): Di-tert-butyl dicarbonate (154 mg, 0.70 mmol) was

added to a solution of 27 (46 mg, 0.07 mmol) in a mixture of freshly

distilled THF (5 mL), NEt₃(1 mL) and H₂O (1 mL). The mixture

was stirred for 7 h at room temp. The organic solvent was evapo-

1

yellow solid. Yield 154 mg, 0.23 mmol, 92%. H NMR (300 MHz,

CDCl₃): δ = 7.53 (s, 2 H, ArH), 7.39 (s, 2 H, ArH), 6.70–6.58 (m, rated under reduced pressure and the residue was taken up in a

6 H, ArH), 4.48 (d, J = 13.6 Hz, 2 H, H_axof ArCH₂Ar), 4.45 (d, mixture of Et₂O (5 mL) and 1  NaOH (5 mL). The organic layer

J = 13.6 Hz, 2 H, H_axof ArCH₂Ar), 3.96 (t, J = 7.2 Hz, 2 H,

was separated, the aqueous phase was extracted with Et₂O

OCH₂CH₂CH₃), 3.92 (t, J = 7.5 Hz, 2 H, OCH₂CH₂CH₃), 3.91– (2ϫ5 mL) and the combined organic layers were washed with 1 

3.76 (m, 4 H, OCH₂CH₂CH₃), 3.24 (d, J = 13.6 Hz, 2 H, H_eqof NaOH (5 mL) and 1  HCl (5 mL), dried with Na₂SO₄and the

ArCH₂Ar), 3.23 (d, J = 13.6 Hz, 2 H, H_eqof ArCH₂Ar), 2.00–1.82

solvents evaporated to dryness to obtain the product as a white

( m , 8 H , O C H ₂C H ₂C H ₃) , 1 . 0 7 – 0 . 9 8 ( m , 1 2 H , solid to be used without further purification. Yield 50 mg,

OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 170.6, 0.066 mmol, 95%. ¹H NMR (300 MHz, CDCl₃): δ = 6.58 (br. s, 11

162.3, 161.4, 156.2, 142.4, 136.5, 135.4, 134.6, 133.5, 130.5, 129.0,

H, ArH and NH), 4.46 (d, J = 13.5 Hz, 2 H, H_axof ArCH₂Ar),

128.3, 123.6, 122.8, 77.1, 76.9, 76.8, 31.5, 31.0, 23.3, 23.2, 4.40 (d, J = 13.4 Hz, 2 H, H_axof ArCH₂Ar), 3.82 (br. s, 8 H,

10.3 ppm. MS (ESI-MS): calcd. for C₄₁H₄₈NO₈631.3; found 726.3

[M – H + 2Na]⁺. C₄₁H₄₈NO₈(681.33): calcd. C 72.22, H 6.95, N

2.05; found C 72.31, H 6.82, N 2.16.

OCH₂CH₂CH₃), 3.20 (d, J = 13.5 Hz, 2 H, H_eqof ArCH₂Ar), 3.11

(d, J = 13.4 Hz, 2 H, H_eqof ArCH₂Ar), 1.94–1.85 (m, 8 H,

OCH₂CH₂CH₃), 1.47 [s, 9 H, CH₃(Boc)], 1.04–0.88 (m, 12 H,

OCH₂CH₂CH₃) ppm. C₄₆H₅₇NO₈(751.41): calcd. C 73.47, H 7.64,

N 1.86; found C 73.50, H 7.61, N 1.90.

5-Amino-25,26,27,28-tetrapropoxycalix[4]arene-17-carboxylic Acid

(27): Hydrazine hydrate (54 µL, 176 mmol) and a catalytic amount

of Pd/C (10 %) were added to a suspension of 26 (150 mg,

0.22 mmol) in ethanol (10 mL). The mixture was heated at reflux

for 4 h, then the catalyst was filtered off and the organic solvent

was evaporated under reduced pressure to obtain the product as a

white solid to be used without further purification. Yield 128 mg,

5-(Boc-Amino)-17-(methoxy-L-alanyl)carbonyl-25,26,27,28-tetra-

propoxycalix[4]arene (31): NEt(iPr)₂(49 µL, 0.28 mmol), PyBOP

(73 mg, 0.17 mmol) and -alanine methyl ester hydrochloride

(24 mg, 0.175 mmol) were added to a solution of 30 (50 mg,

0.07 mmol) in dry DMF (3 mL). The mixture was stirred for 24 h

at room temp. Upon addition of H₂O (3 mL) the product was ob-

1

0.20 mmol, 90%. H NMR (300 MHz, CDCl₃): δ = 7.06 (s, 2 H,

ArH), 6.87 (d, J = 7.8 Hz, 4 H, ArH), 6.75 (t, J = 7.8 Hz, 2 H, tained as a white precipitate which was collected by Büchner fil-

ArH), 5.80 (s, 2 H, ArH), 4.45 (d, J = 13.4 Hz, 2 H, H_axof Ar- tration, washed with H₂O (2ϫ2 mL) and used without further pu-

CH₂Ar), 4.36 (d, J = 13.5 Hz, 2 H, H_axof ArCH₂Ar), 4.25 (br. s, rification. Yield 45 mg, 0.05 mmol, 77%. ¹H NMR (300 MHz,

2 H, NH₂), 3.94–3.80 (m, 6 H, OCH₂CH₂CH₃), 3.67 (t, J = 7.0 Hz, CDCl₃): δ = 6.87 (s, 2 H, ArH), 6.76 (t, J = 6.4 Hz, 4 H, ArH),

2 H, OCH₂CH₂CH₃), 3.19 (d, J = 13.5 Hz, 2 H, H_eqof ArCH₂Ar), 6.71 (d, J = 6.4 Hz, 2 H, ArH), 6.44 (br. s, 1 H, NH), 6.38 (br. s,

3.05 (d, J = 13.4 Hz, 2 H, H_eqof ArCH₂Ar), 1.93–1.81 (m, 8 H, 1 H, NH), 6.33 (s, 2 H, ArH), 4.73 (br. s, 1 H, CH), 4.46 (d, J =

OCH₂CH₂CH₃), 1.07–0.89 (m, 12 H, OCH₂CH₂CH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃/MeOD, 1:1, v/v): δ = 169.4, 159.4, 156.0,

153.4, 135.3, 134.5, 134.3, 133.8, 128.8, 128.2, 127.8, 127.7, 123.8,

121.5, 119.2, 76.2, 76.1, 75.8, 29.9, 22.5, 22.4, 22.2, 9.2, 8.8 ppm.

C₄₁H₄₉NO₆(651.35): calcd. C 75.55, H 7.58, N 2.15; found C

75.62, H 7.50, N 2.18.

13.4 Hz, 2 H, H_axof ArCH₂Ar), 4.38 (d, J = 13.4 Hz, 2 H, H_axof

ArCH₂Ar), 3.90–3.62 (m, 8 H, OCH₂CH₂CH₃), 3.77 (s, 3 H,

OCH₃), 3.20–3.10 (m, 4 H, H_eqof ArCH₂Ar), 1.88 (br. s, 8 H,

OCH₂CH₂CH₃), 1.44 [s, 9 H, CH₃(Boc)], 1.25 [br. s, 3 H,

CH₃(Ala)], 1.05–0.85 (m, 12 H, OCH₂CH₂CH₃) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 159.5, 156.7, 153.9, 153.0, 152.9, 150.2,

135.4, 135.2, 134.8, 128.7, 128.6, 128.4, 126.8, 126.7, 122.1, 121.8,

79.8, 76.7, 76.6, 52.5, 48.3, 30.9, 29.6, 28.3, 23.2, 23.1, 18.5, 10.4,

10.1 ppm. MS (ESI-MS): calcd. for C₅₀H₆₄N₂O₉836.5; found 859.5

[M + Na]⁺. C₅₀H₆₄N₂O₉(836.46): calcd. C 71.74, H 7.71, N 3.35;

found C 71.81, H 7.69, N 3.38.

Compound 28: NEt(iPr)₂(53 µL, 0.31 mmol), N-Cbz--alanine

(34 mg, 0.15 mmol) and PyBOP (140 mg, 0.27 mmol) were added

to a solution of 27 (50 mg, 0.077 mmol) in dry DMF (3 mL). The

mixture was stirred overnight at room temp. Upon addition of H₂O

(3 mL) a precipitate formed which was collected by Büchner fil-

tration. Column chromatography (eluent: hexane/AcOEt, 7:3, v/v)

was carried out on the crude mixture and compound 28 was iso-

lated as the more abundant component as a white powder. Yield

5-Amino-17-(methoxy-L-alanyl)carbonyl-25,26,27,28-tetrapropoxy-

calix[4]arene (32): A sample of 31 (45 mg, 0.05 mmol) was dissolved

in a CH₂Cl₂/TFA/triethylsilane/H₂O (3 mL, 47.5:47.5:2.5:2.5,

v/v/v/v) solution and the mixture was stirred for 3 h at room temp.

The solvents were evaporated in vacuo and the residue was dis-

solved in CH₂Cl₂(3 mL). The organic phase was washed with 5%

NaHCO₃(2 mL) and H₂O (2 mL). The product was obtained as

1

15 mg, 0.024 mmol, 31%. H NMR (300 MHz, CDCl₃): δ = 7.14

(d, J = 7.4 Hz, 2 H, ArH), 7.12 (d, J = 7.4 Hz, 2 H, ArH), 6.98 (t,

J = 7.4 Hz, 2 H, ArH), 6.80 (s, 1 H, NH), 5.62 (s, 2 H, ArH), 5.52

(s, 2 H, ArH), 4.43 (d, J = 14.4 Hz, 2 H, H_axof ArCH₂Ar), 4.42

Eur. J. Org. Chem. 2008, 869–886

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883

L. Baldini, R. Ungaro et al.

FULL PAPER

a white solid and used without further purification. Yield 36 mg,

0.049 mmol, 98%. H NMR (300 MHz, CDCl₃): δ = 7.08 (s, 1 H,

(91 mg, 0.17 mmol) were added to a solution of 30 (55 mg,

0.07 mmol) in dry DMF (3 mL). The mixture was stirred for 5 h at

room temp. Upon addition of H₂O (3 mL) the product was ob-

tained as a white precipitate which was collected by Büchner fil-

tration, washed with H₂O (2ϫ2 mL) and used without further pu-

1

ArH), 7.02 (s, 1 H, ArH), 6.70–6.58 (m, 6 H, ArH), 6.43 (d, J =

7.0 Hz, 1 H, NH), 5.83 (s, 2 H, ArH), 4.65 (quint., J = 7.1 Hz, 1

H, CH), 4.46 (d, J = 13.4 Hz, 2 H, H_axof ArCH₂Ar), 4.35 (d, J =

1 3 . 2 H z , 2 H , H _{a x}o f A r C H ₂A r ) , 3 . 8 7– 3 . 8 0 ( m , 4 H , rification. Yield 47 mg, 0.06 mmol, 84%. M.p. 93–95 °C. ¹H NMR

OCH₂CH₂CH₃), 3.76 (s, 3 H, OCH₃), 3.72–3.70 (m, 4 H,

OCH₂CH₂CH₃), 3.18 (d, J = 13.2 Hz, 2 H, H_eqof ArCH₂Ar), 3.02

(d, J = 13.4 Hz, 2 H, H_eqof ArCH₂Ar), 1.93–1.81 (m, 8 H,

(300 MHz, CDCl₃): δ = 6.82–6.65 (m, 8 H, ArH), 6.47 (br. s, 1 H,

NH), 6.30 (s, 2 H, ArH), 5.68 (br. s, 1 H, NH), 4.46 (d, J = 13.5 Hz,

2 H, H_axof ArCH₂Ar), 4.38 (d, J = 13.4 Hz, 2 H, H_axof Ar-

OCH₂CH₂CH₃), 1.43 [d, J = 7.1 Hz, 3 H, CH₃(Ala)], 0.98–0.90 (m, CH₂Ar), 3.92–3.79 (m, 6 H, OCH₂CH₂CH₃), 3.70 (t, J = 7.2 Hz,

12 H, OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 2 H , O C H ₂C H ₂C H ₃) , 3 . 3 5 ( q , J = 5 . 9 H z , 2 H ,

173.9, 167.2, 159.9, 157.0, 135.6, 135.5, 135.4, 135.3, 134.5, 128.7,

128.6, 128.2, 128.1, 127.2, 126.8, 122.1, 115.3, 77.1, 76.9, 52.5, 48.3,

31.9, 31.1, 23.3, 23.2, 18.6, 10.5, 10.4, 10.3 ppm. C₄₅H₅₆N₂O₇

(736.41): calcd. C 73.34, H 7.66, N 3.80; found C 73.35, H 7.54, N

3.95.

NHCH₂CH₂CH₂CH₃), 3.17 (d, J = 13.4 Hz, 2 H, H_eqof Ar-

CH₂Ar), 3.12 (d, J = 13.5 Hz, 2 H, H_eqof ArCH₂Ar), 1.93–1.84

(m, 8 H, OCH₂CH₂CH₃), 1.53–1.32 (m, 4 H, NHCH₂CH₂CH₂CH₃

and NHCH₂CH₂CH₂CH₃), 1.43 [s, 9 H, CH₃(Boc)], 1.03 (t, J =

7.7 Hz, 3 H, NHCH₂CH₂CH₂CH₃), 0.98–0.91 (m, 12 H,

OCH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 168.1,

159.0, 156.8, 154.1, 153.0, 135.6, 135.0, 134.7, 131.5, 128.7, 128.4,

126.5, 122.1, 79.3, 76.7, 76.6, 76.5, 39.5, 31.7, 30.9, 28.3, 23.3, 23.2,

23.0, 20.0, 13.8, 10.4, 10.0 ppm. MS (ESI-MS): calcd. for

C₅₀H₆₆N₂O₇806.5; found 829.5 [M + Na]⁺. C₅₀H₆₆N₂O₇(806.48):

calcd. C 74.41, H 8.24, N 3.47; found C 74.47, H 8.19, N 3.51.

5-(N-Cbz-L-Alanyl)amino-17-(methoxy-L-alanyl)carbonyl-

25,26,27,28-tetrapropoxycalix[4]arene (33): NEt(iPr)₂(34 µL,

0.19 mmol), N-Cbz--alanine (27 mg, 0.12 mmol) and PyBOP

(51 mg, 0.10 mmol) were added to a solution of 32 (36 mg,

0.05 mmol) in dry DMF (3 mL). The mixture was stirred for 6 h at

room temp. Upon addition of H₂O (3 mL) the product was ob-

tained as a white precipitate which was collected by Büchner fil-

tration, washed with H₂O (2 ϫ 2 mL) and purified by flash

5-Amino-17-butylaminocarbonyl-25,26,27,28-tetrapropoxycalix[4]-

arene (35): Calixarene 34 (47 mg, 0.06 mmol) was dissolved in a

chromatography (hexane/ethyl acetate, 7:3, v/v). Yield 22 mg, CH₂Cl₂/TFA/triethylsilane/H₂O (3 mL, 47.5:47.5:2.5:2.5, v/v/v/v)

1

0.023 mmol, 48%. H NMR (300 MHz, CDCl₃): δ = 8.00 (s, 1 H,

NH), 7.35–7.29 (m, 5 H, Ph), 6.86 (s, 1 H, ArH), 6.80–6.67 (m, 7 solvents were evaporated in vacuo and the residue was dissolved in

H, ArH), 6.39 (s, 1 H, ArH), 6.32 (d, J = 7.3 Hz, 1 H, NH), 6.28 CH₂Cl₂(3 mL). The organic phase was washed with 5% NaHCO₃

(s, 1 H, ArH), 5.62 (d, J = 7.3 Hz, 1 H, NH), 5.10 (s, 2 H, CH₂Ph), (2 mL) and H₂O (2 mL). The product was obtained as an oil and

solution and the mixture was stirred for 4 h at room temp. The

4.68 (br. s, 1 H, CH), 4.46 (d, J = 13.4 Hz, 1 H, H_axof ArCH₂Ar),

4.45 (d, J = 13.5 Hz, 1 H, H_axof ArCH₂Ar), 4.40 (d, J = 13.6 Hz,

1 H, H_axof ArCH₂Ar), 4.39 (d, J = 13.4 Hz, 1 H, H_axof Ar-

CH₂Ar), 4.30 (br. s, 1 H, CH), 3.92–3.71 (m, 8 H, OCH₂CH₂CH₃),

3.76 (s, 3 H, OCH₃), 3.17 (d, J = 13.4 Hz, 1 H, H_eqof ArCH₂Ar),

used without further purification. Yield 40 mg, 0.06 mmol, quanti-

tative. H NMR [300 MHz, CDCl₃/MeOD (4:1, v/v)]: δ = 6.90 (s,

2 H, ArH), 6.64 (d, J = 7.4 Hz, 4 H, ArH), 6.56 (t, J = 7.4 Hz, 2

H, ArH), 5.79 (s, 2 H, ArH), 4.39 (d, J = 13.4 Hz, 2 H, H_axof

ArCH₂Ar), 4.29 (d, J = 13.4 Hz, 2 H, H_axof ArCH₂Ar), 3.80–3.62

1

3.16 (d, J = 13.5 Hz, 1 H, H_eqof ArCH₂Ar), 3.14 (d, J = 13.4 Hz, ( m , 8 H , O C H ₂C H ₂C H ₃) , 3 . 1 8 ( t , J = 7 . 2 H z , 2 H ,

1 H, H_eqof ArCH₂Ar), 3.11 (d, J = 13.6 Hz, 1 H, H_eqof Ar-

CH₂Ar), 1.94–1.82 (m, 8 H, OCH₂CH₂CH₃), 1.39 [d, J = 6.9 Hz,

NHCH₂CH₂CH₂CH₃), 3.10 (d, J = 13.4 Hz, 2 H, H_eqof Ar-

CH₂Ar), 2.96 (d, J = 13.4 Hz, 2 H, H_eqof ArCH₂Ar), 1.86–1.75

6 H, CH₃(Ala)], 1.05–0.99 (m, 6 H, OCH₂CH₂CH₃), 0.96–0.91 (m, (m, 8 H, OCH₂CH₂CH₃), 1.43–1.23 (m, 4 H, NHCH₂CH₂CH₂CH₃

1

6 H, OCH₂CH₂CH₃) ppm. H NMR (600 MHz, [D₆]acetone): δ = and NHCH₂CH₂CH₂CH₃), 0.96–0.83 (m, 15 H, OCH₂CH₂CH₃

9.02 (s, 1 H, NH), 7.84 (d, J = 7.2 Hz, 1 H, NH), 7.61 (s, 2 H,

ArH), 7.44 (d, J = 7.8 Hz, 2 H, Ph), 7.40 (t, J = 7.8 Hz, 2 H, Ph), 159.3, 156.6, 149.9, 139.4, 135.5, 135.1, 134.6, 128.4, 128.0, 126.6,

and NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

7.34 (t, J = 7.8 Hz, 1 H, Ph), 7.27 (s, 1 H, ArH), 7.22 (s, 1 H, ArH),

6.61 (d, J = 7.2 Hz, 1 H, NH), 6.40–6.34 (m, 6 H, ArH), 5.15 (d,

121.8, 115.7, 76.7, 76.6, 76.5, 39.4, 31.4, 30.8, 23.1, 23.0, 20.0, 13.5,

10.2, 10.1, 10.0 ppm. C₄₅H₅₈N₂O₅(706.43): calcd. C 76.45, H 8.27,

J = 12.6 Hz, 1 H, CHHPh), 5.11 (d, J = 12.6 Hz, 1 H, CHHPh), N 3.96; found C 76.51, H 8.22, N 3.99.

4.69 (quint., J = 7.2 Hz, 1 H, CH), 4.54 (d, J = 13.2 Hz, 2 H, H_ax

17-Butylaminocarbonyl-5-propanoylamino-25,26,27,28-tetraprop-

of ArCH₂Ar), 4.49 (d, J = 13.2 Hz, 2 H, H_axof ArCH₂Ar), 4.38

(quint., J = 7.2 Hz, 1 H, CH), 4.11 (t, J = 7.8 Hz, 2 H,

OCH₂CH₂CH₃), 4.01 (t, J = 8.4 Hz, 2 H, OCH₂CH₂CH₃), 3.79 (t,

J = 7.2 Hz, 4 H, OCH₂CH₂CH₃), 3.73 (s, 3 H, OCH₃), 3.27 (d, J

= 13.2 Hz, 2 H, H_eqof ArCH₂Ar), 3.18 (d, J = 13.2 Hz, 1 H, H_eq

of ArCH₂Ar), 3.16 (d, J = 13.2 Hz, 1 H, H_eqof ArCH₂Ar), 2.06–

1.94 (m, 8 H, OCH₂CH₂CH₃), 1.49 [d, J = 7.2 Hz, 3 H, CH₃(Ala)],

1.46 [d, J = 7.2 Hz, 3 H, CH₃(Ala)], 1.13 (t, J = 7.2 Hz, 6 H,

OCH₂CH₂CH₃), 1.00 (t, J = 7.2 Hz, 6 H, OCH₂CH₂CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 173.7, 170.9, 168.8, 159.4, 156.9,

155.7, 154.1, 136.5, 135.6, 135.4, 134.9, 130.6, 128.9, 128.8, 128.5,

128.4, 128.3, 128.1, 128.0, 126.9, 126.2, 123.4, 122.9, 122.3, 77.3,

77.1, 66.8, 52.6, 50.6, 48.5, 31.0, 23.4, 23.3, 23.2, 19.5, 18.5, 10.6,

10.5, 10.1 ppm. MS (MALDI-MS): calcd. for C₅₆H₆₇N₃O₁₀941.5;

found 964.4 [M + Na]⁺, 980.4 [M + K]⁺. C₅₆H₆₇N₃O₁₀(941.48):

calcd. C 71.39, H 7.17, N 4.46; found C 71.46, H 7.08, N 4.48.

oxycalix[4]arene (36): NEt(iPr)₂(52 µL, 0.30 mmol), propionic acid

(13 µL, 0.18 mmol) and PyBOP (62 mg, 0.12 mmol) were added to

a solution of 35 (40 mg, 0.06 mmol) in dry DMF (3 mL). The mix-

ture was stirred for 5 h at room temp. The reaction was quenched

by the addition of 1  HCl (3 mL). The mixture was extracted with

AcOEt (2ϫ3 mL) and the combined organic layers were washed

with a saturated solution of Na₂CO₃(3 mL) and H₂O, dried with

Na₂SO₄and the solvents evaporated to dryness. After flash

chromatography (hexane/EtOAc, 7:3, v/v) pure 36 was obtained as

a white solid. Yield 19 mg, 0.025 mmol, 42%. ¹H NMR (300 MHz,

CDCl₃): δ = 7.56 (s, 1 H, NH), 6.98 (d, J = 7.4 Hz, 4 H, ArH),

6.84 (t, J = 7.4 Hz, 2 H, ArH), 6.55 (s, 2 H, ArH), 6.07 (s, 2 H,

ArH), 5.66 (t, J = 6.1 Hz, 1 H, NH), 4.46 (d, J = 13.5 Hz, 2 H,

H_axof ArCH₂Ar), 4.39 (d, J = 13.5 Hz, 2 H, H_axof ArCH₂Ar),

4.00–3.90 (m, 4 H, OCH₂CH₂CH₃), 3.73 (t, J = 6.9 Hz, 2 H,

OCH₂CH₂CH₃), 3.67 (t, J = 6.8 Hz, 2 H, OCH₂CH₂CH₃), 3.26 (q,

5-(Boc-Amino)-17-butylaminocarbonyl-25,26,27,28-tetrapropoxy- J = 6.1 Hz, 2 H, NHCH₂CH₂CH₂CH₃), 3.15 (d, J = 13.5 Hz, 2 H,

calix[4]arene (34): n-Butylamine (70 µL, 0.70 mmol) and PyBOP H_eqof ArCH₂Ar), 3.14 (d, J = 13.5 Hz, 2 H, H_eqof ArCH₂Ar),

884

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Eur. J. Org. Chem. 2008, 869–886

Chiral Dimeric Capsules from Peptidocalix[4]arenes

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2.19 (q, J = 7.5 Hz, 2 H, COCH₂CH₃), 1.95–1.80 (m, 8 H,

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1.55 (quint., J = 6.9 Hz, 2 H, NHCH₂CH₂CH₂CH₃), 1.36 (sext, J

= 6.9 Hz, 2 H, NHCH₂CH₂CH₂CH₃), 1.10–0.90 (m, 18 H,

OCH₂CH₂CH₃, COCH₂CH₃and NHCH₂CH₂CH₂CH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 172.7, 169.1, 158.4, 157.4, 153.2,

136.6, 135.6, 134.5, 133.9, 131.2, 129.2, 128.9, 128.6, 126.0, 123.5,

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10.7, 10.6, 9.8 ppm. MS (ESI-MS): calcd. for C₄₈H₆₂N₂O₆762.5;

found 785.5 [M + Na]⁺. C₄₈H₆₂N₂O₆(762.46): calcd. C 75.56, H

8.19, N 3.67; found C 75.68, H 8.07, N 3.74.

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Financial contribution from the Ministero dell’Università e Ricerca

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Sensing e Catalisi) is acknowledged. We also thank the Centro

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Received: July 31, 2007

Published Online: December 11, 2007

886

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Article Doi

Self-assembled chiral dimeric capsules from difunctionalized N,C-linked peptidocalix[4]arenes: Scope and limitations

DOI: 10.1002/ejoc.200700943

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