chiral calixarenes

Turk J Chem

33 (2009) , 159 – 200.

c© TUBITAK

doi:10.3906/kim-0901-36

Review

Chiral Calixarenes

Abdulkadir SIRIT1,∗ and Mustafa YILMAZ2

1Selcuk University, Ahmet Kelesoglu Education Faculty, Department of Chemistry,Konya, 42099-TURKEY

e-mail: [email protected] University, Faculty of Science, Department of Chemistry,

Konya, 42031-TURKEYe-mail: [email protected]

Received 23.01.2009

Introduction

Calixarenes, obtained in the condensation reaction of formaldehyde and p-substituted phenols, are often referredto as the third generation of supramolecular receptors after crown ethers and cyclodextrins.1,2 They have 2well-defined rims, an upper rim defined by the para substituents of the phenolic rings and a lower rim definedby the phenolic hydroxyl groups (Figure 1). This excellent skeleton enables calixarenes to act as “molecular

baskets” towards neutral or ionic guests.3

OHOHOH

OH

R RR R

OHOH

RR R R

OH OHLower rim

Upper rim

Figure 1. Representation of calix[4]arenes and designation of the faces.

By comparing with naturally occurring host molecules, such as cyclodextrins, the calix[n]arenes providea very flexible template for building numerous structures with potentially useful host–guest properties. Theeasy accessibility and the selective functionalizations at one of the calix rims have made this class of compoundscompetitive candidates for studying the interactions involved in host–guest recognition as well as useful receptors

∗Corresponding author

159

Chiral Calixarenes, A. SIRIT, M. YILMAZ

in separation processes. Calix[n]arenes are readily converted into a wide range of derivatives containing various

functional groups such as ketone,4 amine, 5 ester,6−8 amide,9−12 alcohol,13,14 ether,15 carboxylic acid,16

crown ether,17 or other functional groups. The complexation properties of these molecules depend on the ringsize of the calix[n]arene, the nature of the groups attached, the number of donor atoms, and the conformationof the macrocycle. Calixarene-based receptors find remarkable applications in molecular recognition studiesconsistent with the principles of host–guest chemistry, phase transfer catalysis, chromatography, ion-selectiveelectrodes, and liquid membrane technology. The chemistry of calixarenes is well documented in the literature,including journal articles, published conference proceedings, books, chapters in books, reviews, patents, doctoraltheses, and reports.18−35

Chiral calixarenes have attracted increasing attention in recent years due to their potential as enan-tioselective artificial receptors and asymmetric catalysts. Two principal approaches have been used for thepreparation of chiral calixarenes. The first one is synthesis of ‘inherently’ chiral calixarenes, built up of achiralmoieties and consequently owe their chirality only to the fact that the calixarene molecule is not planar. In theliterature, several strategies, including fragment condensation, and regio- and stereoselective functionalizationat the lower rim, have been reported for the preparation of inherently chiral calixarenes. The second approachis an attachment of chiral moieties at the upper or lower rim of calixarene macrocycle.

From a practical point of view, the second approach appears to be preferable, because enantiomeri-cally pure derivatives can be obtained relatively easily, provided the derivatization reaction proceeds withoutracemization if homochiral reagents are used. However, the inherently chiral calixarenes generally require morecomplex synthetic procedures and a difficult resolution on an appropriate scale.

Only a few reviews36−43 or chapters in books on chiral calixarenes concerning their synthesis, applications,and properties as well as chiral recognition are available.

This review covers both the synthesis and applications of the chiral calixarenes bearing enantiomericallypure substituents developed by us and other groups and is organized according to the type of chiral unit attachedto the calixarene framework for the synthesis of chiral calixarenes.

In 1987, Shinkai and co-workers synthesized a chiral calixarene derivative 1 for the first time (Figure

2), from the reaction of (S)-1-bromo-2-methylbutane with calix[6]arene-p-hexasulphonate.44,45 Since then, anumber of research groups have incorporated various chiral subunits at either the upper or lower rims of thecalixarene macrocyclic ring. Thus, chiral receptors based on the calixarene platform provide a new approach

Me

O

Me

SO3Na

*

1 n = 42 n = 63 n = 8

n

Figure 2. p−sulfonatocalix[n]arenes bearing (S)-2-methylbutoxy groups.

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for studies of the host–guest chemistry of calixarenes and may have potential applications in the preparation,separation, and analysis of enantiomers and asymmetric synthesis.

Amines and Amino Alcohols

Many approaches have been developed with chiral amino alcohols and amines as chiral sources in the synthesis ofcalixarenes. We have constructed novel chiral mono and diamide derivatives of calix[4]arene from the aminolysisreaction of calix[4]arene diester with appropriate primary amine or amino alcohols (Figure 3) and examined their

binding abilities by UV–Vis absorption and 1 H-NMR spectroscopy.46,47 All chiral receptors have greater K

values toward the enantiomers of phenylethylamine (PEA) than cyclohexylethylamine (CHEA), the nonaromaticanalog of PEA, due to π−π interactions as well as hydrogen bonding. Furthermore, somewhat greater K valueswere obtained for chiral receptors 7-14, bearing the alcohol–OH group. Such an additional functional groupseems to work for better complexation and chiral recognition because of hydrogen bonding with -OH groups. Itseems that chiral calix[4]arenes 4-14 interact with a minimum of 3 of the possible recognition groups (carbonyloxygen, amide nitrogen, phenoxy oxygen, phenyl group, and hydroxy groups) in order to exhibit enantioselectivebinding to the chiral amines. The extraction properties of compounds 9-14 toward selected α -amino acid methylesters were also studied in a liquid–liquid extraction system.

OH

R

O OH O

R R R

O O

OMe R’

OH

R

O OH O

R R R

O O

R’ R’

HN HN OH

NO2

OH

HN OH

Ph

HN OH

Et

HN OH

Ph

4 - 5 6 - 14

R’:

a b c d e

4 R = C(CH3)3, R’ = a5 R = H, R’ = a

6 R = H, R’ = a7 R = C(CH3)3, R’ = b8 R = H, R’ = b9 R = C(CH3)3, R’ = c10 R = H, R’ = c11 R = C(CH3)3, R’ = d12 R = H, R’ = d13 R = C(CH3)3, R’ = e14 R = H, R’ = e

Figure 3. Mono and diamide derivatives of calix[4]arene.

Zheng and co-workers have reported a series of chiral nitrogen-containing calix[4]arene and calix[4]crownderivatives (Figure 4) bearing optically pure amine, 1,2-diphenyl-1,2-oxyamino, αsβ -amino alcohol, and α−β -

diamine groups at the lower rim.13,48−50 Chiral receptors 18, 19, and 23 showed good to excellent chiral recog-nition abilities towards the enantiomers of mandelic acid, dibenzoyltartaric acid, and 2-hydroxy-3-methylbutyricacid. They have also demonstrated that chiral calix[4]arenes (15-17) bearing long tertiary alkyl groups at the

161


upper rim and (S)-1-phenylethylamine groups at the lower rim can form heat-set gels and egg-like vesiclesenantioselectively with D -2,3-dibenzoyltartaric acid in cyclohexane, which is the first example of heat-set gelsresulting from a difference in interactions between 2 component gelators.51

OOHOH

O

HN NH

HH

PhPh

HN

HH

NH HN

HH

NH

OH

NHH

H

Ph

Ph

OH

NHH

H

H

Ph

NH

OH

H

H

HN O

HH

HPh

NH O

H H

O

NH

MeH

Ph

O

NHMe

HPh

OHOH

R RRR

HN O

HHPh Ph

15 R = -C(CH 3)2(CH2)13CH3

16 R = -C(CH3)2(CH2)9CH3

17 R = -C(CH3)2(CH2)5CH3

18 R = -t-Bu

19 - 27

X

X =

19 20 21 22

23 24 25 26 27

2 22

Figure 4. Chiral nitrogen-containing calix[4]arene and calix[4]crown derivatives.

Our group has also described the synthesis of novel chiral calix[4](azoxa)crown ethers 28 and 29 (Figure

5) from the reaction of calix[4]arene diacid chloride with a chiral diamine.52,53 In liquid–liquid extractionexperiments, 29 exhibits selectivity for Li+ among the other alkali metals and a good extraction ability fortransition metal cations, suggesting its potential use in different fields, such as a sensor for ions as well as forchiral molecules.

OR ORO O

OO

N N

O

O

O

PhPhHH

OOMeMeO O MeO O

NHNH

NH

OOMe MeO O MeO O

NH

NHNH2

OOMe MeO O MeO O

NH2

NHNH2

OMeO MeO O OMe

NR

N

RN

O

NR

28 R = H29 R = Bn

32

33 34

*

30 R = Ns31 R = H

Figure 5. Chiral calix[4](azoxa)crown ethers and calix[6]aza-cryptands.

162


Jabin and co-workers synthesized the first enantiopure calix[6]aza-cryptands from 1,3,5-tris-O -methylated

calix[6]arene.54 NMR studies showed that the tetra protonated derivative 30.4H+ displays remarkable host–guest properties towards polar neutral molecules and enantioselective recognition processes with chiral guests.Similarly optically pure calix[6]arenes bearing chiral amino arms 32, 33, and 34 have been synthesized in high

yields from the known symmetrically 1,3,5-trismethylated calix[6]arene.55 The chiral derivative 34 undergoesa conformational change with the 3 ammonium arms, forming a tris-cationic chiral binding site that caps thecavity. The obtained polarized host (34.3H+) behaves as a remarkable endo-receptor for small polar neutralmolecules.

Yilmaz et al. have reported the synthesis of chiral calix[4]arene 36-38 and calix[6]arene 39, 40 (Figures 6

and 7) derivatives possessing phenylalaninol and phenylethylamine substituents.56−58 Liquid–liquid extractionstudies of ligands towards some selected α -amino acid methylesters, amino alcohols, and α -amines displayedgood affinity towards all amino acid species without any remarkable discrimination.

NH

Ph

NH

O

Ph

O

O

O

NH

Ph

NH

Ph

R

R R

R

* **

NH

O

O

OHPh

NH

O

O

OHPh

O

NHO

OHPh

OH

35 R= H36 R= tert-butyl

37 (R)38 (S)

Figure 6. Chiral calix[6]arene derivatives possessing phenylalaninol and phenylethylamine substituents.

NH

Me

N N

N

N N

N

OOO

O

PrPrPr Pr

NH NH

NHNH2NH2

Me **

*OH

NH

Bu

O

Bu

OMe

Ph

41 ( R, R )42 ( R, S )

4 2tt

39 (R)40 (S)

Figure 7. Enantiomerically pure phenylethylamine and dimelamine derivatives of calix[n]arene.

Timmerman, Reinhoudt, and co-workers have reported synthesis and complexation studies of the dime-lamine derivatives 41 and 42 of calix[4]arene starting from the reaction of diamine calix[4]arene with cya-

163


nurchloride, followed by stepwise substitution of the remaining chlorine atoms by ammonia and (R)- or (S)-

methylbenzylamine in several steps.59,60

We have also reported the synthesis of chiral calix[4]arene Schiff base derivatives 43-45 by attachingchiral amines at the upper rim of the calix[4]arene (Figure 8) and their recognition abilities for certain chiral

and achiral amines by a UV–Vis titration method in CHCl3 .61 Chiral receptor 44 showed the enantioselectiverecognition ability toward (R)- and (S)-phenylethylamine (up to KR /KS = 2.67) among all of the chiral hostsstudied and more stable complexes were obtained with n-butylamine compared with 3-morpholinopropylamine.The results revealed that the size/shape-fit concept plays a crucial role in the formation of inclusion complexesof host compounds with guest molecules of various structures.

OH OH OO

H

N

H

NCH3CH3

OH OH OO

H

N

H

NCH3CH3

OH OH OO

H

N

H

N

454443

Figure 8. Calix[4]arene Schiff base derivatives from chiral amines.

Amino Acid Derivatives and Peptides

In biological systems, the cooperative action of peptide hydrogen bonds plays an important role in organization,assembly, and molecular recognition processes.62 On the other hand, specially engineered synthetic peptidesare able to assemble into nanotubes or other supramolecular structures or act as hosts for a variety of guestmolecules. The attachment of R -amino acids or peptides to the calixarene framework can be achieved throughthe terminal amino or carboxylic groups.63

Ungaro et al. have reported the synthesis and inclusion properties of new chiral hosts (Figure 9), having

2 or 4 L-alanine or L-alanyl-L-alanine units at the upper rim N -linked calix[4]arenes.64,65 The water solublepeptidocalix[4]arenes 48 and 52 exhibited noticeable recognition ability toward amino acids and aromaticammonium cations. No inclusion for the very hydrophilic glycine (Gly) and its methyl ester and a very modestchiral discrimination between L-and D -amino acids are observed. A remarkable influence of the rigidity of thecalix[4]arene platform in determining the recognition properties of mobile 48 and rigid cone 52 water solublepeptidocalix[4]arene receptors has been found.

The same group has also described the synthesis and properties of upper rim C-linked peptidocalix[4]arenes55-68 containing 2 or 4 L-alanine or L-phenylalanine units (Figure 10), which represent a novel class of chiralreceptors in that the amino acid units are linked to the calix[4]arene platform through their carboxy groups

rather than through nitrogen as in all previously described N -linked peptidocalix[4]arenes.66,67 In designingthese receptors, it was anticipated that they would show different conformational and binding properties ascompared with their N -linked analogues.

164


NH

NH

O

Me

O

MeO

OMe

NH

NH

O

Me

O

Me O

MeO

NH

NH

O

Me

O

MeO

OMe

NH

NH

O

Me

O

MeO

OMe

O OOO

R

NH

O

Me

O

R

NH

O

Me

O

R

NH

O

Me

O

OOO

O

R

NH

O

Me

O

R

NH

O

Me

O

R

NH

O

Me

O

R

NH

O

Me

O

OOO

OOO

R

NH

O

Me

O

NH

NH

O

Me

O

Me

O

MeO

NH

NH

O

Me

O

Me

O

OMe

OOO

O

NH

O

Me

O

Meo

NH

O

Me

O

OOO

O

OMe

52

49 R = OMe50 R = NH2NH2

51 R = OH52 R = O-

46 R = OMe47 R = OH48 R = O-

53 54

Figure 9. N -linked calix[4]arenes bearing L -alanine units at the upper rim.

NH

NH2

O

*

NH

NH2

O

Ph

*

NH

NPht

O

*

NH

NPht

O

Ph

*

NH

NH

O

O

*

NH

NH

O

Ph O

*

NH

NH

O

O

Ph*

NH

NH

O

Ph O

Ph*

NPht

NH

O

R’

NPht

NH

O

R’

OOO

O

R R

NH2

NH

O

R’

NH2

NH

O

R’

OOO

O

R R

NH

NH

O

R’

NH

NH

O

R’

OOO

O

R R

R R

OO

55 R1 = Me R =

56 R1 = Bn R =

57 R1= Me, R = H58 R1= Bn, R = H

59 R1 = Me R =

60 R1 = Bn R =

61 R1 = Me, R = H62 R1 = Bn, R = H

63 R1 = Me, R2 = Me R =

64 R1 = Bn, R2 = Me R =

65 R 1 = Me, R2 = Ph R =

66 R 1 = Bn, R2 = Ph R =

67 R1 = Me, R2 = Me 68 R1 = Bn, R2 = Me

22

Figure 10. C-linked peptidocalix[4]arenes containing L -alanine or L -phenylalanine units.

165


Interestingly, some of the upper rim bridged N -linked peptidocalix[4]arenes (e.g., 69) behaved as van-comycin mimics (Figure 11) and showed promising antibiotic activity toward gram-positive bacterial strands as a

consequence of their ability to bind the D -alanyl-D -alanine (D -ala-D -ala) terminal part of peptoglycans68,69

while 2 neutral macrobicyclic anion receptors 70 and 71 display good complexation ability for carboxylateanions.70

OOO

O

NH

NH

O

O

NH

NH

O

O

X

OOO

O

O ONH

NHNH

NH

NH

O O

70 X= CH71 X= N

69

Figure 11. Upper rim bridged N -linked peptidocalix[4]arenes.

NH

NHR

Tos

O

OOHOH

O

NH

NH

O

R

Tos

NH

NH

O

R

Tos

NH

NHR

Tos

O

OOHOH

O

NH

NH

O

CH3

Tos

NH

NHCH3

Tos

O

O OO O

OO O

O

NH

NH

Tos

O

R

NH

NH

Tos

OR

NH

NH

Tos

OR

NH

NH

Tos

O

R

O

NH

R’

O

O

NH

R’

O

OHOH

* *

72 a - i

* *

73 a - i

* *

74

75 b, d, f, h, i

a: R= Me (D-Ala)b: R= Me (L-Ala)c: R= iPr (D-Val)d: R= iPr (L-Val)e: R= CH2Ph (D-Phe)f: R= CH2Ph (L-Phe)g: R= iBu (D-Leu)h: R= iBu (L-Leu)i: R= CH(CH 3)CH2CH3 (L-IsoLeu)

76 R’ = OAc77 R’ = OH

Figure 12. Chiral calix[4]arenes functionalized with α -hydroxyamide and amino acid functions.

166


New chiral calix[4]arenes functionalized at the lower rim with α -hydroxyamide and amino acid functionshave been prepared (Figure 12) as a class of receptors selective for anions that are bound through hydrogen

bonding with the NH group.71−73 Host–guest complexation properties of these ligands towards various anionshave been studied by 1 H-NMR spectroscopy. It was found that the chiral calix[4]arene derivatives 72-74 and77 might be suitable for the synthesis of hydrophobic neutral anion receptors, which are able to bind anions ina 1:1 stoichiometry through hydrogen bonding. High binding constants are observed and better selectivity isobtained for N -tosyl-(L)-alaninate presumably due to additional πtπ interactions between the tosyl groups.

Bisurea calix[4]arene-based receptors 78-83 possessing amino acid moieties were obtained by meansof nucleophilic addition reactions of the methyl esters of glycine, L-alanine, or L-isoleucine with isocyana-tocalix[4]arenes (Figure 13). Ligand 81, having alanine residues close to the urea binding groups, shows a

remarkable ability to recognize D − N -acetylphenylalaninate from the corresponding L-isomer.74

OOHOH

O

NH

NH

O

NH

NH

O

O O

R R

O O

OOO

O

NH

NH

O

NH

NH

O

O O

R R

O O

78 R = H80 R = Me82 R = sec-Bu

79 R = H81 R = Me83 R = sec-Bu

Figure 13. Bisurea calix[4]arene-based receptors possessing amino acid moieties.

Huang and co-workers have reported that calixarenes or their diamino derivatives were reacted with N -Boc-L-amino acids or N -chloroacetyl amino acid ester to give the calixarene diamide (Figure 14) (84-89) or

diester (Figure 15) (90-92) derivatives.75,76

Bu

OCH2COR

Bu

OMe

-HNOC2H5

O

-HN

O OMe

-HN

O OMe

-HN

O OMe

N

O

OMe

t

3

t

84 R = 85 R =

86 R = 87 R =

88 R =

84 - 88

Figure 14. Chiral calix[6]arene diamide derivatives containing amino acid residues.

167


OOOH OH

NH NH

RR

O O

OOOH OH

R R

O OOOH

OH OH

R

O

OH OH

OHOH

O

RO O

R

O

R

O

RO O

O

NHBoc NHBoc

Me

NHBoc

Me

Me NHBoc

Ph

NHBoc

SMe

NHBoc

Me

Me

NHBoc

O

O

Ph

NHBoc

OPh

NHBoc

O

O

Ph

N

89 a - f 90 b-e, g, h 91 f 92

a b c d e f

g h i j

Boc

R =

R =

Figure 15. Chiral calix[4]arene amide and ester derivatives containing N -Boc-L -amino acids.

Mono, di, and tetrasubstituted chiral calix[4]arene derivatives bearing amino acid residues (93-97) atthe lower rim have been prepared (Figure 16) to investigate possible hydrogen-bonding motifs with OH and

amidic functions.77

O

OO O

R RO O

RO RO

-HN

O

Ph

OMe

OOH OH

OH

O

NH

O

Ph

OMe

OOR O

OR

O O

NH

O OMe

Ph NH

O

Ph

MeO

-HNO

OMeCH2CH(CH3)2 97 R =

96 R =

H

Me

93 R =

95

94 R =

Figure 16. Mono, di, and tetrasubstituted chiral calix[4]arene derivatives bearing amino acid subunits.

Rudkevich et al. have described the design and synthesis of calix[4]arene amino acids (Figure 17) 98-103,which were used as construction blocks to assemble nanoscale, multivalent entities—calix–peptides 104 and 105and calix–peptide-dendrimers 106 and 107.78

Neri et al. have described a series of N -linked tetrapeptidocalix[4]arene diversomers (Figure 18), 108-123, by coupling of a cone calix[4]arene tetracarboxylic acid chloride with tetrapeptides obtained in a parallel

fashion.79 The inhibition activity of tetrapeptidocalix[4]arenes towards tissue and microbial transglutaminasewas evaluated by in vitro assays with a labeled substrate.

168


O

N

O

OOO

OO

O

OEtEtO

EtO

CH2)4

NR

H

H

OO

N

OO

OO

OO

O

EtOOEt

OEt

CH2)4

H

NR

O

N

O

OOO

OO

O

OEtEtO

EtO

CH2)4

NH

H

O

OH

N

CH2)4

N RH

H

N

CH2)4

N RH

H

O

NHCH2)4

O

NMeO

O

OO

OOO

OO

O

OEt

EtO

EtO

O

O

OO

O

O

O

O

EtO

EtO

EtO

H

(

R1O

98 R = C(O)(CH2)6CH3 , R1 = Bn

99 R = Cbz, R1 = Me100 R = Cbz, R1 = p-t-Bu-C6H4

101 R = Boc, R1 = Me102 R = C(O)(CH2)6CH3 , R

1 = H103 R = H.CF3C(O)OH , R1 = Me

104 R = C(O)(CH2)6CH3 , R1 = Me

105 R = Boc , R1 = Me106 R = C(O)(CH2)6CH3

107 R = Boc

(

R1O

( (

(

Figure 17. Calix[4]arene amino acids, calix–peptides, and calix–peptide-dendrimers.

AA4

AA3

AA2

AA1

NH

AA4

AA3

AA2

AA1

NH

AA4

AA3

AA2

AA1

NH

AA4

AA3

AA2

AA1

NH

OOO

OPrPr

Pr Pr

O

O O

O

MeO

MeO OMe

OMe Gly Phe Gly Tyr

Gly Phe Gly PheGly Phe Leu Phe

Gly Yrp Ala Tyr

Gly Leu Val PheGly Phe Val Phe

Gly Val Leu Phe

Gly Leu Gly LysGly Val Phe Tyr

Gly Gly Phe Asp

Gly Trp Ala TyrGly Ala Leu Tyr

Gly Phe Val Tyr

Gly Leu Phe Phe

Gly Leu Gly PheGly Val Phe Phe

AA1 AA2 AA3 AA4 ORNH2

OOO

O

PrPrPr

NHNH

NHNH

AlaAla Ala

Ala

Pr

108109110111112113114115116117118119120121122123

108 - 123

124

Figure 18. N -linked tetrapeptido- and alanine-substituted calix[4]arene derivatives.

Synthesis of alanine-substituted calix[4]arene (Figure 18) 124 from the acid chloride of Fmoc-alanine

has been described by Shuker et al.80 The dimerization and binding properties of compound 124 were alsoinvestigated by NMR spectroscopy. It was reported that this is the first example of a calix[4]arene derivativethat self-associates in polar, protic solvent.

Water-soluble calix[4]resorcinarenes (Figure 19) 128-133 with 3- and 4-hydroxyproline substituent groupsare evaluated as chiral NMR solvating agents on a series of monosubstituted phenyl-containing compounds. Theysuggested that the substrates interact with the calixresorcinarene through insertion of the aromatic ring into thecavity. Cationic, anionic, and neutral substrates were examined, and all exhibited enantiomeric discriminationin the 1 H-NMR spectrum with one or more of the calixresorcinarenes.81−83

169


R

R R

R

X

X

X

X

OHOH

OH

OH

OHOH

OH

OH

HH

H H N COO-

CH2

H

NCH2

COOH NCH2

COOH

OH

NCH2

COOH

OH

NCH2

COOH

OH

NCH2

COOH

OH

125 - 133

R= (CH2)2SO3Na

125 126 127 128

-H -CH3-OH

+

X=

X=

129 130 131 132 133

Figure 19. Water-soluble calix[4]resorcinarenes.

Warner et al. described the first chiral separations of 3 binaphthyl derivatives (BNHP, BINOL, andBNA) using (N −L-alaninoacyl)calix[4]arene (135) and (N −L-valinoacyl)calix[4]arene (Figure 20) (136) as

pseudostationary phases in capillary electrophoresis.84,85 All 3 binaphthyl derivatives were baseline resolvedwhen chiral selector 136 or a mixture of sodium dodecyl sulfate and 135 was used as an additive to the buffer.The results showed that the optimum buffer pH was 11, and the buffer concentration was 40 mM Na2HPO4

for the separation.

New types of chiral calix[4](aza)crowns (137, 138) containing L-valine were synthesized by Wu and co-

workers.86 Chiral recognition properties of host 137 was studied by 1 H- and 13C-NMR, and UV spectroscopy.It was found that host 138 exhibited different recognition ability towards the (R)- or (S)-mandelic acid and(L)- or (D)-dibenzoyltartaric acid.

R’

RO

****NH

O

O

R

R’

O

NH

O

O

R

R’

O

NH

O

O

O

R’

R

NH

O

O

NHNH

N

RO O

OO OHOH

134 R = Me; R’ = OBut

135 R = CH(CH3)2; R’ = OH136 R = Me; R’ = OH

137 R= Me138 R= H

Figure 20. N -linked amino acid-substituted calix[4]arene and calix[4]azacrown derivatives.

Wenzel and co-workers have prepared a series of chiral calix[4]arenes 139-148, by attaching opticallypure amino acid esters of alanine, valine, leucine, and proline (Figure 21) through the phenolic oxygen atoms

and calix[4]resorcarenes with primary and secondary amines and examined as CSAs in NMR spectroscopy.87

Although there were a few examples when enantiomeric discrimination occurred in the 1 H-NMR spectra ofsubstrates, the calix[4]arenes and calix[4]resorcarenes that were synthesized were generally unsuccessful atproducing the intended effect.

170


Bu

O

NH

O

O

RO

O

N

OH

Me

Me Ph

N

Bu

O

O

O

OMe

OH

CH2

OH

R

NR’’R’

143 R = Methyl; R’ = -CH2Ph; R’’ = -CH(CH3)3Ph

144 R = Methyl; R’ = -CH3; R’’ = -CH(CH)3C10H7

145 R = Methyl; R’ = -CH(CH3)Ph; R’’ = -CH(CH)3Ph

147 R = Heptyl; R’ = -CH2Ph; R’’ = -CH(CH)3Ph

148 R =Heptyl; R’ = -CH3; R’’ = -CH(CH)3C10H7

146

4

t

139 R = -CH3

140 R = -CH(CH3)2

141 R = -CH2CH(CH3)2

4

4

t

142

4

143-145, 147-148

Figure 21. Chiral calix[4]arenes bearing optically pure amino acid esters of alanine, valine, leucine, and proline.

Two-armed chiral calix[4]arenes (149-151) functionalized at the lower rim with L-tryptophan units have

been prepared by He and co-workers (Figure 22).88 The enantioselective recognition of these receptors towards

a series of chiral carboxylates has been studied by fluorescence titration and 1H-NMR spectroscopy. Receptor149 has been demonstrated to be a highly selective fluorescent sensor for N -Boc-protected alanine anion and150 reveals good enantioselective recognition ability towards the enantiomers of mandelate. According to theresults, a relatively rigid structure, good structural preorganization, steric effects, and multiple hydrogen bondsinduce the enantioselective recognition ability of 149 and 150.

NH

O

NH

O

O

OMe

NH

O

NH

O

O

MeO

OHOH OO OHOH

NH

NH

O

NHO

NHBoc

NH

NH

O

NHO

NHBoc

NHNH

NH

NH

O

NHBoc

O

O

NH

NH

ONHBoc

O

O

OHOH

150 151149

Figure 22. Two-armed chiral calix[4]arenes functionalized with L -tryptophan units.

Cheng and co-workers have reported the synthesis of a series of chiral calix[4]arene derivatives by the

reaction of calix[4]arene diacid dichloride with various amino acid derivatives (Figure 23).89−91 Receptors 152-154 were found to bind much more favorably with (R)-methyl lactate than with its (S)-enantiomer by usingthe quartz crystal microbalance (QCM) method, and thus render it as a good new candidate for chiral gas sensor

171


coatings, whereas receptor 159 was found to be an efficient receptor for the biologically important phosphatemolecule whose neutral receptors are only scarcely reported (Figure 24).

ON

HNH O

H

O

NH

NH

O

O

HH

O

NH

NH

O

O

HH

O

S

RS

NH NHOO

O O

OMe OMe

OOHOH

O

NHO

EtS O

OMe

O

NHO

SEtO

OMe

O OHOH

RO

O

RO

OOHOH

152-154

152 R* =

153 R* =

154 R* =

156 R = (CH 2)2

157 R = (CH 2)4

158 R = p-CH 2C6H4CH2

155

**

Figure 23. Dicyclopeptide-bearing calix[4]arene derivatives.

O

NHO

S

O

NH O

SCO2CH3

H3CO2C

OHOH

OHOH

OHOH

O

NH

O

S

CO2CH3

ONH

O

S

CO2CH3

O

NH

O

S

H3CO2C

O

NH

O

S

H3CO2C

* ** *

**

159 160

Figure 24. Cystine-containing calix[4]arene derivatives.

Neri and colleagues have described the synthesis of some new optically active calix[4]arene derivatives

bearing chiral pendant units, which include amino acids, and pinene-like and binaphthyl groups (Figure 25).92

The application of these derivatives in enantioselective catalysis was studied by testing the catalytic activitiesof the corresponding Ti(IV)/calixarene complexes, prepared in situ, in an asymmetric aldol reaction. Unfortu-nately, only limited enantioselectivities were observed.

Huang et al. have synthesized the Boc-L-proline-appended calix[4]arene derivatives 170-175 (Figure 26)

and used them for the preparation of pure m-dimethylamino substituted inherently chiral calix[4]arenes.93−95

Their applications as novel bifunctional organocatalysts in the enantioselective direct aldol reaction were alsoreported. It was found that the inherently chiral catalysts 173 and 175 could promote the aldol reactionbetween 4-nitrobenzaldehyde and cyclohexanone in the presence of acetic acid in high yields and with goodenantioselectivities.

172


OHOH OOH

OR

O

NH

O OMe

OBu

O

NH

O

OBu

OBu

ONH

OMe NH

NH

O

OMe

O

ROOR OHOH

CH2

CH2

NHO

O

OBu

MeO

HNO

HNO

161-165

t

t

t

161 162 163 164 165

t

166-169 166 167 168 169

Figure 25. Optically active calix[4]arene derivatives bearing amino acids, pinene-like, and binaphthyl groups.

OOO O

NNH

O

N(CH3)2

R

OOO O

NNH

O

(CH3)2N

R

OOO O

NNH

O

R

172 R = Boc173 R = H

174 R = Boc175 R = H

170 R = H171 R = NO2

Boc

Figure 26. Boc-L -proline-appended calix[4]arene derivatives.

He et al. have constructed a series of chiral calix[4]arenes (176-179) (Figure 27) containing hydrazide,dansyl, and anthracene groups and examined them for their enantioselective recognition abilities by the fluo-rescence and 1 H-NMR spectra in CHCl3 .96,97 The results indicate that both 176 and 177 exhibit excellentenantioselectivities towards N -protected alanine or phenylalanine anions due to the cooperative act of the hy-drazide and amide in the binding amino acid anion by multiple hydrogen bonds, whereas receptors 178 and 179exhibit good chiral recognition abilities towards the enantiomers of D - and L-tetrabutylammonium malate, andformed a 1:1 complex between the host and guest.

Similarly 2 chiral chromogenic sensors 180 and 181 containing both thiourea and amino acid bindingunits have been synthesized and examined for their chiral anion-binding abilities by UV/Vis absorption and 1 H-

NMR spectroscopy.98 The results reveal that 180 exhibits good enantioselective recognition for the enantiomersof the α -phenylglycine anion. Moreover, the marked color changes observed for the complexation of 180 withthe chiral anions reveal that receptor 180 could be used as a good chiral chromogenic chemosensor for theenantiomers of the α -phenylglycine anion.

173


* ** *

N

ONH

CH R L

O

NH

NH

S OO

N

ONH

CHRL

O

NH

NH

S OO

OOH OH

O

ONH

CH R L

O

NH

NH

ONH

CHRL

O

NH

NH

OOH OH

O

* *

NH

NO2

ONH

CH R L

O

NH

NH

S

NH

NO2

ONH

CHRL

O

NH

NH

S

OOH OH

O

176 R = CH3

177 R = PhCH2

178 R = CH3

179 R = PhCH2

180 R = CH3

181 R = PhCH2

Figure 27. Chiral calix[4]arenes containing hydrazide, dansyl and anthracene groups.

The synthesis of a new enantiomerically pure resorcinarene by linking L-valine tert butylamide to the8 hydroxy groups of a resorc[4]arene was described by Schurig and co-workers.99,100 The chiral macrocyclicproduct was chemically bonded to a poly(hydro)dimethylsiloxane by hydrosilylation using a platinum catalyst(Figure 28). The resulting chiral polysiloxane Chirasil-Calix 182 can be used as chiral stationary phase (CSP)in capillary gas chromatography.

182

Figure 28. Chirasil-Calix as chiral stationary phase (CSP) in capillary gas chromatography.

174


Fluorescent Groups

Calixarene-based enantioselective fluorescence receptors are generally composed of a fluorophore and a chiralmoiety attached to the calix[4]arene skeleton and organic fluorophores are usually arranged in proximity tohydrogen bonding and chiral centers in the host molecule in such a way that binding of the guest species resultsin quenching of the fluorescence.101 The use of fluorescently labeled chiral calixarenes for enantioselectiverecognition of chiral amines and amino alcohols have attracted considerable interest because such receptorspotentially provide a real-time technique that can be used to determine the enantiomeric composition of chiralmolecules.102−105

The excellent chiral recognition ability of 1,1-binaphthocrowns was utilized in calixarene chemistry forthe first time by Kubo et al., who prepared chromogenic receptors (S)-183 and 184 containing indophenol

indicator units as part of the calixarene core (Figure 29).106−108 Ligand (S)-183 and to some extent (S)-184was disclosed to selectively recognize (R)-phenylglycinol in EtOH solution associated with a remarkable changeof color, thus representing the first chiral sensor for the colorimetric determination of amine enantiomers.

NN OH OHX OO

OO OOO O 183 n= 0

184 n= 1

X=

n

Figure 29. Chiral calix[4]arene derivatives containing indophenol indicator units.

Chiral calixarene derivatives (185-187) bearing (S)-di-2-naphthylprolinol and (R/S)-1-(9-anthryl)-

2,2,2-trifluoroethanol groups have been synthesized by Diamond and co-workers (Figure 30).109−111 One ofthese, an (S)-di-2-naphthylprolinol tetramer 185, is shown to exhibit significant ability to discriminate betweenenantiomers of 1-phenylethylamine (PEA), phenylglycinol, and norephedrine on the basis of the quenching ofthe (S)-di-2-naphthylprolinol fluorescence emission in chloroform. In these guest molecules, the common featureis the positioning of hydrogen bonding sites and a chiral center immediately adjacent to an aryl ring. The arylring is known to be a crucial feature, as cyclohexylethylamine, the nonaromatic analogue of phenylethylamine,has no quenching effect at all.

Similarly, a propranolol amide derivative of p-allylcalix[4]arene 188 in which binding sites and the chiralcenter separated from the fluorescent naphthyl groups by an additional ether group has been designed tobehave as a molecular sensor capable of distinguishing chiral amines on the basis of their shape and chirality.112

This ligand was found to successfully discriminate between the enantiomers of phenylalaninol, which possesses amethylene spacer between its aromatic moiety and chiral center. It was also found that a significant enhancementin the observed enantiomeric discrimination would occur on binding of the calixarene with potassium cation.

175


CF3

Bu

O

O

Bu

O

O OH O

H

3

ttBu

O

O N

OH

4

t

CF3O

Bu

O

O

Bu

O

O OHH

42

t t

O

O N

O

OH

185 186 187

4

188

Figure 30. Chiral calixarene derivatives bearing (S)-di-2-naphthylprolinol and

(R/S)-1-(9-anthryl)-2,2,2-trifluoroethanol groups.

Recently Huang et al. reported the synthesis of a series of tri-O -alkylated and tetra-O -alkylated inher-ently chiral fluorescent calix[4]crowns in the cone and partial cone conformations respectively using (S)-BINOL

attached calix[4]arenes (189-194, 198-200) (Figure 31).113−115 One of the tetra-O -alkylated inherently chiralfluorescent calix[4]crown-6 in the partial cone conformation 197 was found to exhibit considerable enantiose-lective recognition capability towards the enantiomers of leucinol.

O OH

OO

O

O O

RO

OO

OOH

O

O

OO

O O

n nn

O

O

OO

O O

O

O

OH

O

O

O

OH

O

OO

O O

OHO

189 n =1190 n = 2191 n = 3

192 n =1193 n = 2194 n = 3

195 n =1196 n = 2197 n =3

198 n =1199 n = 2200 n =3

R= nPr, nBu

n

Figure 31. Chiral fluorescent calix[4]crowns in the cone and partial cone conformations.

The same group have also presented the preparation of chiral calix[4]arenes 201-204 derived from(S)-BINOL or (R)-phenylglycinol (Figure 32) and employed in the synthesis of a series of inherently chi-

ral calix[4]quinolines on the upper rim.116 Their optical resolutions were conveniently achieved through theseparation of their diastereomers.

176


N

OO PrOPrO Pr Pr

CH3

COO

OH

N

OO PrOPrO Pr Pr

CH3

NH

O

OH

N

OO PrOPrO Pr Pr

COO

O PrOPrO Pr

N

CH3

O Pr

COOOH

But ButBut

But ButBut

202 (diastereoisomers)


But ButBut


But ButBut


Figure 32. Chiral calix[4]arenes derived from (S)-BINOL and (R)-phenylglycinol.

Chiral calix[5]arenes bearing a binaphthyl crown on the lower rim, (R)-, (S)-205 and (R)-, (S)-206

were successfully synthesized (Figure 33).117 The complexes [(R)-205.Cu2+ ] and [(S)-205.Cu2+ ] were usedas binary hosts to recognize carbohydrates. The fluorescent titration experiments showed that the binary hostscan selectively recognize D -(+)-gluconic acid δ -lactone between various carbohydrates.

O O

O

O OO O O

O

O O

O

OH OO OH OH

O

205 206

Figure 33. Chiral calix[5]arenes bearing a binaphthyl crown unit at the lower rim.

New chiral upper and lower rim (R)-binaphthyl-bridged calix[4]arenes (207-212) have been synthesized

by exploiting the selective functionalization of the calix[4]arene skeleton (Figure 34).118 Their complexationproperties toward neutral molecules, alkali metal, and silver(I) cations have also been explored.

177


OOO

O

NH NH

O

NH NH

O

OO

O O

O

NH NH

OO O

OOH OH

O

OOO

O

NH NHR’ R’

O OO O

ONH NH

O

NHNH

OO

OOH OH

O

O O

207 R’ = H208 R’ = I209 R’ =

210 211 212

Figure 34. (R)-binaphthyl-bridged chiral calix[4]arenes.

Sugars

Model O -glycosylation reactions at either rim of calix[4]arenes are described by Dondoni and Ungaro with the

aim of providing access to a new family of carbohydrate-containing calixarene derivatives named calixsugars.119,120

One or 2 sugar moieties (D -mannofuranose and D -glucopyranose) were introduced at the lower rim of thecalix[4]arene (213-218) by glycosylation of the phenolic hydroxyl groups by means of a Mitsunobu reac-tion whereas tetrapropoxy calix[4]arenes bearing 2 or 4 hydroxymethyl groups at the upper rim were cou-pled with perbenzoylated thioethyl D -galactoside and D -lactoside and β -linked bis- and tetrakis-O -galactosylcalix[4]arenes were obtained (219-222) (Figure 35). The galactose-containing calixsugars showed some affinitytoward charged carbohydrates and dihydrogen phosphate anion.

O O

O O

OO

OH OHOH

O

O

O O OOO O

O O

OO

OH OH

O

O OROR

ORROO

RORO

OR

OR

OOH OH

O

O RO

OR

OROR

O

RORO

OR

OR

O

OH OH

O OOO

OO

OHOH

OH

OHO

OOH

OH

OH

OH

PrPr Pr

Pr

OOH

OH

OH

OH

OO

OOH

OH

OHO

OHOH

OH

OHO

OO

OHOH

OH

O OOO

Pr Pr PrPr

O

OOH

OH

OH

OHO

OOH

OH

OH

OH

O

O

OH

OHOH

OH

OO

OHOH

OH

OH

O OOO

PrPr Pr

Pr

OOH

OH

OH

OH

OO

OOH

OH

OHO

OHOH

OH

OHO

OO

OHOH

OH

O OOO

O

PrPr Pr

Pr

213 214 215R = Ac216R = H

219

220

221 222

217R = Ac218R = H

Figure 35. Carbohydrate-containing calixarene derivatives.

Lhotak and co-workers have described new calixarene–saccharide conjugates 223-225 using the reactionbetween the appropriate acyl chloride and an amino calix[4]arene or an aminosaccharide derivative (Figure

178


36).121 The introduction of sugar moieties into the lower rim of calix[4]arene leads to novel receptors, theusefulness of which has been demonstrated by their interaction with various monosaccharide derivatives.

O

OO

OOO

OH OH

O O

NH

ONH

O

OO

OO

OAc

OH OH

O O

NH

AcO

AcO

OAc

OAc

O

OAc

AcO

AcO

OAc

OAc

ONH

NH

OH OH

O O

O

OH

OH

OH

OH

OH

NHO

OH

OH

OH

OH

OH

223 224 225

Figure 36. Calix[4]arene–saccharide conjugates.

Consoli and co-workers have also described an efficient approach for the introduction of 8 mono- ordisaccharide sugar moieties (D -glucose, N -acetyl-D -glucosamine, D -galactose, L-fucose, D -maltose, and D -

cellobiose) at the upper rim of calix[8]arene, using thioureido linkers (Figure 37).122 It was reported that theglycocalix[8]arenes 226-237 may act as biomimetic carbohydrate systems and as hosts for highly polar organicmolecules.

NH

NH

S

sugar

CH2

OPr

O

OR

OR

RORO

O

N

OR

RORO H

Ac

O

OR

OR

RO

OR

O

OR

OR

ROO

O

OR

OR

RORO

OCH3

OROR

OR

O

OR

OR

ROO

O

OR

OR

RORO

8

226 R = Ac227 R = H

228 R = Ac229 R = H

230 R = Ac231 R = H

232 R = Ac233 R = H

234 R = Ac235 R = H

236 R = Ac237 R = H

226-237

Figure 37. Calix[8]arene bearing sugar moieties.

The synthesis and biological activity of new tetrakis(mannopyranosyl) calix[4]arenes (238-241) with adeepened cavity were described using the Sonogashira reaction for the assembly of the sugar moieties onto thecalix[4]arene scaffolds (Figure 38).123

179


O

ORRO

O

O

OR

RO

O

OOR

RORO

RO

O

OORRO

RORO

O

OOO

O

RR R

R

OR

OR

OR OR

1

11

1

238 R = Ac; R1 = H239 R= Ac; R1 = tBu

240 R = R1 = H241 R = H; R1 = tBu

Figure 38. Tetrakis(mannopyranosyl) calix[4]arenes.

Bitter, Kubinyi, and co-workers have produced novel chromogenic 1,3-calix[4](crown-6) derivatives (Fig-ure 39) composed of 1,1’-binaphthyl, α − D -glucoside, and D -mannitol moieties in the crown ether ring and

supplied with 2,4-dinitrophenylazo indicator groups.124,125 Receptors 242e and 243g exhibited noticeable chiralrecognitions toward α -methylbenzylamine enantiomers. The UV fluorescence of (R)-242e/(S)-242e arisingfrom the binaphthyl moiety is quenched by K+ ions, but not by the amine guests, showing that the interactionbetween the binaphthyl group and the complexed amines is weak.

OR

RR R

R

ORO O

O

O

O

O

OOR

O

RR R

R

OO

OO

O

O

O OMe

ORO

ORO

RR R

R

OO

OO

OO

OO

OR

N NO2N

NO2

NO

242

1

1 1

1

2 2

243

11 1

1

2 2

244

22

a: R1, R2, R3 = Hb: R1, R3 = But, R2 = Hc: R1, R3 = H, R2 = Me

d: R1, R3 = H, R2 = Pre: R1, R3 = H, R2 = Bnf: R1, R3 = H, R2 = CH2COOEt

g: R1, R3 = H, R2 =

h: R1, R3 = H, R2 =

Figure 39. Chromogenic 1,3-calix[4](crown-6) derivatives from 1,1’-binaphthyl, α − D -glucoside and D -mannitol

moieties.

The synthesis of molecular capsules using non-covalent interactions is a very attractive area of supramolec-ular chemistry. Rebek et al. described the optically active tetraureas 247-258, prepared through reaction ofthe tetraamine calix[4]arene with the appropriate isocyanates derived from amino acid methyl esters, which

have self-complementary recognition sites and assemble into dimeric structures (Figure 40).126,127

180


O OO

NH NHNHNH

O

NHR 2

O

NH

O

R 2

O

NHR 2

O

NHR 2

R 1R 1 R 1

R 1

OO O

NHNH NH NH

O

NH

R 2

O

NH

O

R 2

O

NH

R 2

O

NH

R 2

R 1R 1

R 1R 1

OC10H21

OC10H21

OC10H21

NH NHNHNH

OC10H21

NHR

O

NH

O

R

O

NH

R

O

NHR

O

OH

O

OH

O

OH

H

O

OH

O

OH

O

OH

Ph

O

OH

Ph

O

OH

OO

C4H9

C4H9

OO

Ph

Ph

R =

251 252 253 254

255 256 257 258

O-t-Bu

R1 = C10H21 R2 = C6H4-p-C7H14

R2 = SO2C6H4-pCH3

R2 =

R2 =

245

R1 = C10H21

R1 = C10H21

R1 = C10H21

R1 = C10H21

R1 = C10H21

246

247

248

249

250 R2 =

R2 =

Figure 40. Tetraureas of calix[4]arene derivatives and calixarene-based dimers.

Tartaric Acid Derivatives

Tartaric acid derivatives are useful building blocks for the synthesis of chiral calixarenes. The attachment ofhomochiral residues to the lower rim provides a calixarene with novel properties and the synthesis of calixcrownshas been reported. For example, tartaric ester chloroacetates can be easily prepared by the reactions ofchloroacetyl chloride with esters of tartaric acid. Attaching of these chiral fragments to the platforms ofcalix[4]arenes affords a new kind of chiral calix[4]arene derivatives 259-261 (Figure 41).128

OOHOH

O

O

O O OO

OR’R’OO

OOHOH

O

O

O O OO

OR’R’OO

OOHOH

O

O

O O OO

OR’R’OO

** ** **

261a-d260a-f259a-f

a: (L-), R’= Et;b: (L-), R’= n-Pr;c: (L-), R’= i-Pr;d: (L-), R’= n-Bu;e: (D-), R’= Et;f: (D-), R’= i-Pr

Figure 41. Chiral calix[4]arenes bearing tartaric ester moieties.

181


Our group has also described the synthesis of new chiral calix[4]arene derivatives 263-267 containingtartaric acid ester moieties at the lower rim and various functionalities including aldehyde, nitro and Schiffbase at the upper rim (Figure 42).129,130 The chiral recognition capabilities of calix[4]arene derivatives toward

the guests, 1,2-propanediol and α -aminoacid esters, were investigated by 1 H-NMR and UV-vis spectroscopy.Chiral hosts 262 and 263 showed enantiomeric recognition toward rac-serine methyl ester hydrochloride and1,2-propanediol, respectively, due to the multiple hydrogen bonding. On the other hand, chiral selectors 265-267 show good recognition ability for the enantiomers of phenylalanine and alanine methyl ester hydrochlorides(up to KD /KL = 4.36, ΔΔG0 = –3.65 kJ mol−1). The D/L-enantioselectivities are found to be highlysensitive to the Schiff base moiety attached to the upper rim of calix[4]arene and the shape of the substitutedgroup in amino acid derivatives. The steric hindrance between the ammonium cation and Schiff base moietyaround the stereogenic centre of the host may play an important role in chiral recognition and is expected tobe minimized for the D -isomer in all cases. Therefore, the D -isomers of amino acid ester hydrochlorides formmore favorable complexes with the chiral selectors than the L-isomers.

O O OO

OO

OO

OOOH OH

RR

O O OO

OO

OO

OO

OH OH

H

O

H

O

Me

Me

Me

NH

O O OO

OO

OO

OOOH OH

N

H

R R

265 R =

266 R =

267 R =

262 R = H263 R = NO2

264

Figure 42. Tartaric ester derivatives of calix[4]arenes with various functionalities including aldehyde, nitro and Schiff

base at the upper rim.

Menthone Derivatives

The synthesis of new chiral calix[n ]arenes 268-271 was reported by Schurig et al. similar to the one-potprocedure described by Gutsche and co-workers using (p-hydroxy-phenyl)-menthone and (-)-menthone (Figure

43).131,132 Calix[n ]arenes with different ring sizes were obtained in reasonable yields.

O

OHn

OH

PP

OOO O

O OR R

Pr-i

MePr-i

Me

268 (n=5)269 (n=6)270 (n=8)

271

8

272 R=

273 R=

Figure 43. Calix[n ]arenes from (p-hydroxy-phenyl)-menthone and (-)-menthone.

182


Chiral p-tert -butyl-calix[4]arene bisphosphites (272-273) have been synthesized by the reaction of p-tert -butyl-calix[4]arene and the phosphorodichloridites, ROPCl2 [R = (1S ,2R ,5R)-(+)-iso-menthyl or (1R ,2S ,5R)-

(-)-menthyl.133

Lopez and co-workers have investigated the complex formation between the antibiotic levofloxacin anda series of chiral calix[4]arene derivatives 274-279 possessing 2 (+)-isomenthyl substituents at the lower rim

(Figure 44).134

O i-Pr

Me

Oi-Pr

Me

OOHOH

O

RRR

R

274: R= H275: R= CH3

276: R= tBu277: R= CH2CHCH2

278: R= COCH3

279: R= NO2

Figure 44. Chiral calix[4]arene derivatives possessing (+)-isomenthyl substituents.

Cinchona Alkaloids

Cinchona alkaloids have served extensively as the primary source of effective chiral catalysts and resolvingagents. These inexpensive commercially available alkaloids can be used as chiral residues in the synthesis ofcalixarenes. Recently, the synthesis of the first calixarene-based chiral phase-transfer catalysts derived fromcinchona alkaloids has been achieved by our group in 2 steps from p-tert -butylcalix[4]arene (Figure 45).135

The catalytic efficiency of the chiral calix[4]arenes 280-282 was evaluated by carrying out the phase transferalkylation of N -(diphenylmethylene)glycine ethyl ester with benzyl bromide. Benzylation of glycine imine usingcalix[4]arene-based dimeric catalyst 280 as a chiral phase-transfer catalyst in toluene/CHCl3 mixture (7:3 v/v)at 0 ◦C gave the best enantioselectivities up to 57% ee and yields in the presence of aqueous NaOH.

The synthesis and chromatographic evaluation of novel carbamate and urea-linked cinchona-calixarenehybrid-type receptors 283-286 and chiral stationary phases (287-290) being derived from 9-amino(9-deoxy)-quinine (AQN), 9-amino(9-deoxy)-epiquinine (eAQN), quinine (QN) and its corresponding C9-epimer (eQN)

were described (Figure 45).136,137 The receptors display complementary enantiomer separation profiles in termsof elution order, chiral substrate specificity, and mobile phase characteristics, indicating the existence of 2 dis-tinct chiral recognition mechanisms. The QN-and AQN-derived CSPs 288 and 290 showed enantioselectivitiesfor open-chained amino acids, preferentially binding the (S)-enantiomers. In contrast, the eQN and eAQNcongeners 287 and 289 exhibited broad chiral recognition capacity for open-chained as well as cyclic aminoacids, and preferential binding of the (R)-enantiomers.

183


N

X

N

H

O NH

O

OOO

O

S

N

X

N

H

O NH

O

OOO

O

Br Br

N+

N

OH

O

N+

N

OH

OOH

nn

OH

289 8S,9S X = NH

290 8S,9R X = NH

silica

89

283 8S, 9R X = O

284 8S, 9S X = O

89

285 8S, 9R X = NH

286 8S, 9S X = NH

287 8S,9S X = O

288 8S,9R X = O

280 n = 1281 n = 2282 n = 3

Figure 45. Chiral calix[4]arenes from cinchona alkaloids as chiral phase-transfer catalysts and stationary phases.

Camphor Sulfonyl Chloride

Camphor sulfonyl chloride has also been employed for the introduction of chirality into calixarenes. Kalchenkoand co-workers have reported the preparation of chiral calix[4]arenes (291-295) from the reaction of calix[4]arenemonoalkyl ethers with 1(S)-camphor-10-sulfonyl chloride and (R)- or (S)−N -(1-phenylethyl)bromoacetamides

(Figure 46).138−140 Enantiomerically pure inherently chiral calix[4]arene derivatives 294d,e and 295d,e havebeen synthesized using chiral receptors 291d,e in preparative yields and high diastereomeric excess.

R

R

R

R OAlk OH

OX

OH

R

R

R

R OAlk XO

OH

OH

R

R

R

R OAlk OH

OH

OX

R

R

R

R OAlk XO

OH

OY

R

R

R

R OAlk XO

OY

OH

291a-e

a: R= H, Alk= i-Pr, X= SO2-(1S)-Camphorb: R= t-Bu Alk= Me, X= SO2-(1S)-Camphorc: R= t-Bu Alk= i-Pr, X= SO2-(1S)-Camphord: R= t-Bu Alk= Me, X= (S) CH2C(O)NHCH(Ph)Mee: R= t-Bu Alk= Me, X= (R) CH2C(O)NHCH(Ph)Me

292a-c 293a-c

Y= C(O)NHC(O)CCl3

295d-e294d-e

Figure 46. Chiral calix[4]arenes from camphor sulfonyl chloride.

184


Shimizu et al. have prepared the chiral calix[4]arene derivatives 297 and 298 bearing a chiral residue(camphorsulfonyl group) for the optical resolution of racemic inherently chiral wide rim ABCD-type calix[4]arene

296 fixed in a cone conformation (Figure 47).141 The chiral calix[4]arene 296 was used as an organocatalystin asymmetric Michael addition reactions of thiophenols.

O Pr

Bu2N

O PrO Pr

OH

O Pr O Pr

Bu2N

O PrO Pr

OX*

O Pr OPr

NBu2

OPrOPr

OX*

OPr

O2S O

X* =

296 297 298

Figure 47. Inherently chiral calix[4]arene derivatives bearing camphor sulfonyl group.

OH

O

tBu

tBu

tBu

tBuBu

Bu

O O

OO

O2SO

OH

OH OH

OHOH

O

OR’

OR

OH OH

OHOH

CH2

CH2

OH

OH

O

NN OO

OO2S

O

SO2

O

R’O

OH

OR

NN OO

OH

O2SO

O2SO

t

t

299300

R= R’=H

R= R’=

301

302

303

304 R = , R’ = H

305 R = H , R’ =

Figure 48. Chiral derivatives of the 1,10-phenanthroline-bridged calix[6]arene.

Luning et al. have investigated several approaches to chiral derivatives of the 1,10-phenanthroline-bridgedcalix[6]arene, and a series of new chiral calix[6]arenes has been synthesized (Figure 48).142 The calixarenes 299-

305 carrying chiral substituents (camphorsulfonyl, myrtanyl) have been prepared using enantiomerically pure

185


reagents. All compounds have been tested as ligands for copper ions in the CuI-catalyzed cyclopropanation ofstyrene and indene but most exhibited selectivities were only marginal.

Epoxides and Glycidyl groups

For the first time, Neri and co-workers reported calixarenes bearing chiral glycidyl groups at the lower rimby treatment of p-tert-butylcalix[4]arene and p-tert -butylcalix[6]arene with glycidyl tosylate.143 Regio- andstereoselective ring-opening reaction of 307 with amines led to chiral β -aminoalcohols (308 and 309) (Figure49).

O

O

O

OOHOH OO

OHOH

NR2 R2N

OHOH

O

O

O

O OH 2

306 307 308309

R = HR = Me

Figure 49. Calixarenes bearing chiral glycidyl groups at the lower rim.

A new series of chiral calix[4]arenes bearing β -amino alcohol groups have been synthesized by conductingthrough the binding of glycidyl groups followed by the regioselective opening by 2 different amines (Figure

50).14 In the presence of [Ru(p-cymene)Cl2 ]2 , the monofunctionalized ligands 313 and 314 proved to beuseful catalysts in the asymmetric transfer hydrogenation of acetophenone and showed good enantioselectivities(ee max = 90%) and very good conversions (conversion max = 97%).

O

O

O

O

R R

OO

nPr nPr

RR

OO

R R

OO

nPr nPr

NHNH

OHOH

Ph Ph

RR

O Bu

O

nPr

O

R R

OO

nPr nPr

R

Bu

O

nPr

O

Bu Bu

OO

nPr nPr

Bu

NH

OH

R’

310 : R = t-Bu311 : R = H

315 R = t-Bu316 R = H

312

t

313 R’ = -benzyl314 R’ = -cyclohexanemethyl

t

t

t t

Figure 50. Chiral calix[4]arenes bearing glycidyl groups as chiral catalysts.

186


We have also used (R)-styrene oxide as a chiral source in the synthesis of chiral calix[4]azacrown ethers

317-320 (Figure 51).144,145 The chiral recognition of these receptors towards the enantiomers of carboxylic

acids and α -amino acid esters has been studied by 1 H-NMR spectroscopy.

Chiral selectors 318 and 319 showed strong binding and some chiral recognition ability for the enan-tiomers of racemic carboxylic acids and α -amino acid esters, respectively, whereas 317 exhibited different chiralrecognition abilities towards both enantiomers of carboxylic acids and α -amino acid esters. The molar ratio andthe association constants of the chiral hosts with each of the enantiomers of guest molecules were determined byusing Job plots and a nonlinear least-squares fitting method, respectively. The results indicate that the multiplehydrogen bonding, steric hindrance, structural rigidity or flexibility and π –π stacking between the aromaticgroups may be responsible for the enantiomeric recognition.

OR

N

O

O

O

O

OR

O

OR

N

O

O

O

O

OR

317 R = H318 R = Me

319 R = H320 R = Me

Figure 51. Chiral calix[4]azacrown ethers selectors from (R)-styrene oxide as a chiral source.

Ethyl Lactate

Recently, Barretta et al. reported a series of ethyl lactate derivatives 321-323 of p-tert -butylcalix[4]arene aschiral solvating agent (CSA) (Figure 52) for the differentiation of the NMR spectra of enantiomeric mixtures of

amino acid derivatives.146 The origin of enantiodiscrimination in solution was investigated by NMR spectroscopyand comparison with model chiral auxiliaries.

OH O

OO

OH O

OO

O

O

OH O O O

OO N

O

H OO

R

R

ButBut

2

ButBut

2

But But But But

322 323 R = Me324 R = NO 2

321

Figure 52. Ethyl lactate derivatives of p-tert -butylcalix[4]arene as chiral solvating agents.

187


Guanidinium Salts

Monolayers of the amphiphilic calix[4]arene derivatives (323-325) bearing chiral bicyclic guanidinium on thesurface of pure water and of aqueous subphases containing L-phenylalanine or D -phenylalanine (L/D -Phe)were studied by film balance measurements (Figure 53). The results indicate that 325-327 can form stablemonolayers at the air–water interface and their capacities of the enantioselective recognition for L/D -Phe

depend on their molecular structures.147,148

OOHOH

OH

N

NH

NH

OH

OOHOH

OH

N

NH

NH

O

Sit-Bu

Ph

Ph

OOHOH

O

N

NH

NH

O

Si

t-Bu

Ph

Ph

HN

N

NH

O

Si

Bu-tPh

Ph

327

Cl

326

Cl

ClCl

325

+-

-

++

-+

-

Figure 53. Calix[4]arene derivatives bearing chiral bicyclic guanidinium moieties.

Cyclodextrins

A new type of calix[4]arene-capped [3-(2-O − β -cyclodextrin)-2-hydroxypropoxy]-propylsilyl-appended silicaparticles has been successfully synthesized and used as chiral stationary phase (CSP) to separate chiral drugs in

HPLC.149 This new type of CSP 328 has a chiral selector with 2 recognition sites: calix[4]arene and β -CD. TheC4CD-HPS has shown excellent selectivity for the separation of aromatic positional isomers and enantiomersof chiral aromatic compounds due to the cooperative functioning of calix[4]arenes and β -CDs (Figure 54).

O

O

OH OMe

O

O

OOH

NH

OHOHOH

OH

OHOHOH

OH

O

O

OH OMe

O

O

OOH

NH

OH O

OO

3

O

O

O

SiO

BrCH2CO O

3

z

O

OCCH2BrO y

O

BrO

x

328

CH2OH CH2OH

6

CH2OH CH2OH

6

329 330

silica

Figure 54. β -cyclodextrin-based chiral calixarene derivatives.

188


Reinhoudt and co-workers have described the preparation of novel host molecules 329 and 330 fromreaction of the secondary hydroxy face of heptakis(6-0-tert-butyldimethylsilyl) β -cyclodextrin with alpha-bromotolunitrile, methylation of the remaining C(2)-hydroxys, conversion of the cyano group to the aminomethyl

group, and reductive coupling with formylcalix[4]arene followed by desilylation.150 The cyclodextrin-calix[4]arenereceptor molecules 329 and 330 were found to be very effective hosts for the fluorescent dyes 1-anilino-8-naphthalenesulfonate and 2-p-toluidino-6- naphthalene-sulfonate and the strongly increased binding capacity isattributed to the additional environmental shielding of the guest by the upper rim of the calix[4]arene, whichcan move over the secondary hydroxy face of the cyclodextrin cavity.

The syntheses of novel calix[4]arene-tethered mono- (331) and bis(beta-cyclodextrin) (332) and theirmolecular recognition behavior with fluorescence dyes, i.e. acridine red (AR) and sodium 2-(p−toluidino)-6-naphthalenesulfonate (TNS), as well as some structurally related guests, i.e. methyl orange (MO), ethyl orange(EO), tropaeolin OO (TOO), brilliant green (BG), crystal violet (CV), and rhodamine B (RhB), in aqueous

buffer solution were presented by Liu, Inoue, and co-workers (Figure 55).151

OOH OH

N

O

NH2

OOH OH

N

O

N

331

But ButButBut

332

Figure 55. Mono and bis β -cyclodextrin-based chiral calixarene derivatives for molecular recognition of fluorescence

dyes.

Miscellaneous

In order to provide tools for investigations of amphotericin B (AmB) ion channels, new conjugates bearing

a calix[4]arene scaffold covalently linked to 4 amphotericin B molecules were synthesized (Figure 56).152 Theantifungal activity of the conjugates 333 and 334 was superior or similar to that of native amphotericin B, withminimal inhibitory concentration values of 0.10 and 0.25 μM, respectively. Investigation of the hemotoxicityalso revealed that these macromolecules are 10 times less toxic than native AmB.

Thondorf et al. have prepared the chiral derivatives of a mesitylene-based calix[4]arene 335 and 336known to exist in the 1,3-alternate conformation by the attachment of homochiral residues to the 4 exo-hydroxygroups (Figure 56).153

In order to develop calixarene-based podands shaped as potent drug dispensers, 2 penicillin arms havebeen grafted at the lower rim of the p-tert -butylcalix[4]arene (Figure 57), giving a new kind of podand (337),

which was fully characterized.154

189


R

O

O

O OH OH

OH

OH OH

OHMe OH

OCO2H

Me

OH

O

Me

O Me

OHN

OH

N

ONH

OO

O

R

OR

OR

R

Me

*NH

O Me

333 R = H334 R = t-Bu

4

*335 R =

336 R =

Figure 56. Conjugates bearing a calix[4]arene scaffold covalently linked to amphotericin B and mesitylene-based

calix[4]arenes.

N N

SH

H

OO

O

OH

N

HO

OO

N

S

O O

HH

O

O

O

OOHOH

337

Figure 57. Penicillin grafted p-tert -butylcalix[4]arene.

Kalchenko and co-workers have described that the chiral calix[4]arene alpha-aminophosphonic acids338d and 339d were obtained through diastereoselective Pudovik-type addition of sodium ethyl phosphitesto the chiral calixarene imines (338a and 339a), removal of chiral auxiliary groups, and mild dealkylation of

phosphonate fragments (Figure 58).155 The diacids obtained show inhibitory activity toward porcine kidneyalkaline phosphatase that depends considerably on the absolute configuration of the α -carbon atoms.

Recently Haino et al. synthesized a calix[5]arene-based artificial receptor 340 capped with a chiral macro-cycle and showed strong binding towards ethyltrimethylammonium derivatives via cation-π and/or hydrogen

bonding interactions (Figure 59). 156

Parisi et al. have also reported that p-tert -butylcalix[5]arenes 341 and 342 in a fixed cone conformation,endowed with a urea functionality at the upper rim (Figure 59), behave as remarkably efficient receptors of α -amino acids and biogenic amines, which are bound with one end of the chain within the π -basic cavity (primary

recognition site) and the other grasped by the secondary hydrogen bonding donor/acceptor binding site.157

190


OH

OH

R

OO Pr Pr

OH

OH

R

R

OO Pr Pr

P NHO

EtO

EtO Me

Ph

P NH2

OEtO

EtO

P NH2

OOH

OH

N

Me

Ph

*

*

*

*

*

a: R=

b: R=

c: R=

d: R=

338 339

Figure 58. Chiral calix[4]arene alpha-aminophosphonic acids.

O

O

NH

O

NH

O

O

NH

O

NH

NH

NH

NH

NH

OHOH

OH

OHOH

OO NH

OR

OR O

R

OR

OR

NHO

RPh

340

*

341 R = Me (R)-342 R = Me (S)-

Figure 59. Chiral calix[5]arene-based artificial receptors.

Recently, Wenzel and co-workers introduced a water-soluble tetra L-prolinylmethyl derivative of tetrasul-fonated calix[4]resorcarene 343 as an effective chiral NMR solvating agent for compounds with bicyclic aromatic

or indole rings (Figure 60).158 It was found that the bicyclic substrates have larger association constants withthe calix[4]resorcarene than similar phenyl-containing compounds. Substantial enantiomeric discrimination is

observed for several resonances in the 1 H-NMR spectra of these substrates.

N

OHOH

CH2

OH

O

CH

CH2

CH2

SO3

N

O O

O

EtO

4

343

4

344

Figure 60. Chiral calix[4]resorcinarenes from L -proline derivatives.

191


Harrison and co-workers have also reported the synthesis and structural characterization of a calix[4]resor-

cinarene based molecule that has helical chirality in the solid state.159 The calix[4]resorcinarene 344 has chiralL-proline ethyl ester substituents positioned perpendicular to the cavity (Figure 60).

Tomaselli et al. have produced the first example of (salen) MnIII and UO2 complexes (345 and 346)

containing a chiral calix[4]arene unit in the ligand framework.160 (Salen) MnIII calix[4]arene complexes wereemployed as catalysts in epoxidation reactions of styrene, dihydronaphtalene and of some standard cis-β -alkylstyrenes and high enantioselectivity up to 72% ee has been obtained.

M

N

NO

O

O O

O

O

Pr

Pr

Pr

Pr

M

N

NO Ph

PhO

O O

O

O

Pr

Pr

PrPr

N

N N

OO

OO

MeMe

N

M= UO2, Mn

345 346

347

Figure 61. Chiral calix[4]arene-metal complexes as chiral catalysts.

Regnouf-de-Vains et al. have introduced the non-complexing chiral (S)-2-methylbutyl substituent closeto the complexing site of a bis[(bipyridinyl)methoxy]-calixarene podand (347), resulting in the induction of an

enantiomeric excess of ca. 30% in the corresponding Cu(I) complex.161

Leeuwen, Kamer, and co-workers have introduced the first chiral calix[4]arene-modified ligands that

induce high enantioselectivity in metal-catalyzed asymmetric reactions.162 Chiral calixarene-based diphosphiteligands 348-351 have been obtained via lower-rim functionalization of the p-tert -butylcalix[4]arene core. Highenantiomeric excess (up to 94%) and good activities were obtained in the rhodium-catalyzed asymmetrichydrogenation of prochiral olefins with TADDOL-containing diphosphites 350 and 351 (Figure 62).

OOO

PO

P

OO

PClO

OO

O

O

OPCl

PhPh

PhPh

PCl =O

O

348 (R)349 (S)

350 (R,R)351 (S,S)

Figure 62. Chiral calixarene-based diphosphite ligands.

192


Consoli et al. have reported the first example of the chiral calix[4]arenes 352a-d and 353a-d bearing

thymine, adenine, cytosine, guanine 2’-deoxynucleotide residues via phosphoester linkage (Figure 63).163,164

Preliminary studies about their assembling in apolar solvent and host properties toward biologically interestingguests are also reported.

N

NH

O

O

N

N

N

N

NH2

N

N

O

NH2

N

N

N

NH

O

NH2

OBOH

O

OO

OH

O O

O

P OOH

O O

OBOH

O

O

O

P OOH

OBOH

O

O

P OOH

O

352a-d 353a-d

a B=

b B=

c B=

d B=

Figure 63. Nucleotide-calixarene conjugates via phosphoester linkage.

Bonini and co-workers have introduced the first example of an enantioselective preparation of a chiralcalix[4]arene bis-epoxide 354 via a direct asymmetric reaction on the parent 1,3-diformyl calix[4]arene inexcellent chemical yield and >99% ee, and its enantiospecific conversion to the corresponding bis-dioxolane355 (Figure 64).165

O

O

O

O

OO OO

HH

HHOO

OO OO

HH

354 (R,R), (R,R) 355 (R,R), (R,R)

Figure 64. Chiral calix[4]arene bis-epoxide and bis-dioxolane derivatives.

Matt et al. have reported the synthesis of chiral diphosphine and phosphinite calix[4]arenes 356-362and used them in allylic alkylation with 67% ee and hydrogenation with 48% ee. Despite these poor transfersof chirality, they obtained excellent results in terms of conversion (100%).166,167

193


OOOOR

NHO

MeHPh

Ph2P PPh2

Pd

BF4

Me

OOOOR

NHO

MeHPh

Ph2P PPh2

Rh

BF4

ButBut But

But

356 R = H357 R = SiMe3

ButBut But

But

358 R = H359 R = SiMe3

360 R = CH2C(O)NHC*H(Me)Ph

OHOOOOChol

OPh2P OPh2P

O

Ph2P OPh2P

O

OCholO

OOHOO

But But ButBut But But But

But

Chol = 12

34 5

6

361 362

Figure 65. Chiral diphosphine and phosphinite calix[4]arenes.

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