Synthesis and preliminary studies on novel enantiopure crown ethers containing an alkyl diarylphosphinate or a proton-ionizable diarylphosphinic acid unit

Article abstract of DOI:10.1016/j.tet.2008.07.111

This paper reports the synthesis, characterization and electronic circular dichroism (ECD) spectroscopic studies of a new type of crown ethers and their achiral analogues containing a tetrahedral phosphorous centre. The synthetic routes to the two chiral phosphinate derivatives [(R,R)-10 and (R,R)-11] were similar, starting from the earlier reported ethyl bis(2-hydroxyphenyl)phosphinate and the unreported methyl bis(2-hydroxyphenyl)phosphinate, respectively. The enantiopure crown ether containing phosphinic acid unit (R,R)-14 was obtained by hydrolysis of the phosphinates (R,R)-10 and (R,R)-11, respectively. ECD spectroscopy was used for investigation of the chiroptical properties as well as complex formation ability of the novel enantiopure ligands. Owing to the presence of the aryl substituents the ECD spectra are rich in bands in the ¹B_b, ¹L_a and ¹L_b regions (190-250 nm and 260-330 nm, respectively). In the case of (R,R)-14, a solvent dependent conformational behaviour was observed due to the strong dimer or aggregate forming ability of the POOH groups. This finding was supported by theoretical calculation of the monomer and the dimer forms. Phosphinates (R,R)-10 and (R,R)-11 form complexes with α-phenylethylammonium perchlorate (PEA) and α-(1-naphthyl)ethyl ammonium perchlorate (NEA) but do not discriminate between their enantiomers. All three chiral crown ethers bind strongly cations of ionic radii <～1 A?.

Full text of DOI:10.1016/j.tet.2008.07.111

Tetrahedron 64 (2008) 10107–10115
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and preliminary studies on novel enantiopure crown ethers containing
an alkyl diarylphosphinate or a proton-ionizable diarylphosphinic acid unitq
a,
b,
c
b
a
c
*
´
Peter Huszthy
, Viktor Farkas , Tunde Toth , Gyorgy Szekely , Miklos Hollosi
¨ ¨
´ ´ ´ ´
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, PO Box 91, Hungary
b Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, PO Box 91, Hungary
c
´
Laboratory for Chiroptical Structure Analysis, Institute of Chemistry, Eo¨tvo¨s Lorand University, H-1518 Budapest, 112 PO Box 32, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2008
Received in revised form 16 July 2008
Accepted 31 July 2008
Available online 6 August 2008
This paper reports the synthesis, characterization and electronic circular dichroism (ECD) spectroscopic
studies of a new type of crown ethers and their achiral analogues containing a tetrahedral phosphorous
centre. The synthetic routes to the two chiral phosphinate derivatives [(R,R)-10 and (R,R)-11] were
similar, starting from the earlier reported ethyl bis(2-hydroxyphenyl)phosphinate and the unreported
methyl bis(2-hydroxyphenyl)phosphinate, respectively. The enantiopure crown ether containing phos-
phinic acid unit (R,R)-14 was obtained by hydrolysis of the phosphinates (R,R)-10 and (R,R)-11, re-
spectively. ECD spectroscopy was used for investigation of the chiroptical properties as well as complex
formation ability of the novel enantiopure ligands. Owing to the presence of the aryl substituents the
ECD spectra are rich in bands in the 1Bb, 1La and 1Lb regions (190–250 nm and 260–330 nm, respectively).
In the case of (R,R)-14, a solvent dependent conformational behaviour was observed due to the strong
dimer or aggregate forming ability of the POOH groups. This finding was supported by theoretical cal-
culation of the monomer and the dimer forms. Phosphinates (R,R)-10 and (R,R)-11 form complexes with
a
-phenylethylammonium perchlorate (PEA) and a-(1-naphthyl)ethyl ammonium perchlorate (NEA) but
do not discriminate between their enantiomers. All three chiral crown ethers bind strongly cations of
ionic radii <w1 Å.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
membrane in both complexed and uncomplexed forms, otherwise
it leaks into the aqueous phase and it is not available further as
Proton-ionizable crown ethers have received a great deal of
attention, because at pH values higher than their pKa, they are
mostly ionized to ligand anions, which increase the cation–ligand
complex stability with enhancement of selectivity, and avoid the
need for a counter anion in cation transport through various
membrane systems or in solvent extraction.1–3 The latter feature is
very advantageous especially in the case of practical separations
where the transport of hydrophilic aqueous phase anions, such as
chloride, nitrate and sulfate should be avoided.2
Using proton-ionizable crown ethers as carriers in an aqueous
source phase–lipophilic membrane–aqueous receiving phase sys-
tem the transport is mostly pH dependent, so it can be turned on
and off by adjusting the pH.3 The proton-ionizable crown ether
carrier should be lipophilic enough to stay in the organic
a carrier.3 Our interest has been focused on proton-ionizable
macrocycles in which the acidic unit is part of the macroring, thus
after deprotonation the negatively charged heteroatom (usually
oxygen or nitrogen) is in the coordination sphere, which surrounds
the complexed cation.4–6
There has always been a strong demand to prepare proton-
ionizable crown compounds, which can dissociate to ligand anions
at relatively low pH values. These acidic proton-ionizable macro-
cycles can also be used to transport some heavy metal cations and
organic primary ammonium ions from a source phase of relatively
low pH value.3 More than two decades ago Bradshaw and co-
workers prepared the achiral and racemic proton-ionizable ligands
1 and rac-2, respectively, containing a fairly acidic dialkylhy-
drogenphosphate unit (see Fig. 1).7 The lipophilic ionophore rac-2
showed a reasonable transport of alkali and some heavy metal
cations in an aqueous source phase–dichloromethane bulk mem-
brane–aqueous receiving phase system.8
q
Preliminary results presented at the Second International Symposium on
In connection with our present work it is noteworthy to mention
that natural ionophores such as valinomycin, monactin, dinactin,
monensin, lasalocid, salinomycin, nigericin, narasin and many
others are optically active compounds and their stereostructure
Macrocyclic and Supramolecular Chemistry, Salice Terme, Italy, 24–28 June, 2007.
* Corresponding author. Tel.: þ36 1 463 1071; fax: þ36 1 463 3297.
E-mail address: huszthy@mail.bme.hu (P. Huszthy).
URL: http://www.och.bme.hu/org
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.111

10108
P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
O
P
more resistant to both acids and bases so their applications can be
R3
R2
R3
R2
O
O
wider. The aromatic rings of macrocycles (R,R)-14 and 15 readily
undergo electrophilic substitution and by introducing appropriate
substituents into them the acidity of the OH proton, the lipo-
philicity, the complexation properties and the photophysical be-
haviour of the latter macrocycles can favourably be altered.
ECD spectroscopy proved to be a simple and powerful tool for
monitoring the steric structure, enantiomeric recognition and cat-
ion selectivity of chiral pyridino-, phenazino-, acridino-18-crown-6
ethers and other ligands.17 Preliminary ECD spectroscopic studies
on the novel chiral crown compounds (R,R)-10, (R,R)-11 and (R,R)-
14 are also reported here.
*
*
*
*
OH
O
O
O
O
R1
1: R1=R2=R3=H
rac-2: R1=octyl, R2=R3=H
(S,S)-3: R1=R2=H, R3=Me
(S,S)-4: R1=R3=H, R2=Me
(S,S)-5: R1=R2=H, R3=octyl
(S,S)-6: R1=R3=H, R2=octyl
Figure 1. Schematics of the reported proton-ionizable crown ethers containing a dia-
lkylhydrogenphosphate moiety.
2. Results and discussion
2.1. Synthesis
plays a crucial role in the selective transport of biologically im-
portant metal cations through biomembranes.9,10 It has been
reported that the stereostructure of optically active artificial host
molecules also plays an important role in binding, solvent extrac-
tion and transport of metal cations.11–13 Motivated by the latter
findings we prepared recently the enantiopure proton-ionizable
crown ethers (S,S)-3–(S,S)-6 (see Fig. 1) containing a dialkylhy-
drogenphosphate moiety.6
Mastryukova and co-workers reported the pKa values of some
substituted diarylphosphinic acids (7–9 see Fig. 2) determined by
potentiometry in three different (7% EtOH–93% H2O, 50% EtOH–50%
H2O, 80% EtOH–20% H2O) mixtures of ethanol and water.14 These
values in the order of the above mixtures are pKa of 7: 2.47, 3.66,
4.45; pKa of 8: 2.32, 3.43, 4.24; pKa of 9: 1.86, not given, 3.48.
As an extension of our research in order to find crown ether type
host molecules possessing enhanced selectivity for both the en-
antiomers of protonated primary amines and metal cations in
binding, solvent extraction, membrane transport and other studies,
we prepared novel enantiopure macrocycles (R,R)-10, (R,R)-11 and
their achiral parent compounds 12, 13 by hydrolysis of the latter
esters (R,R)-14 and 15 containing the acidic diarylphosphinic acid
moiety (see Fig. 3). Novel proton-ionizable ligands (R,R)-14 and 15
seem to have several advantageous features compared to the
reported ones 1–(S,S)-6 (see Fig. 1) possessing the dialkylhy-
drogenphosphate unit. The two aromatic rings make the pseudo-
18-crown-6 framework more rigid conferring higher selectivity in
the molecular recognition process.15,16 Ligands (R,R)-14 and 15 are
The enantiopure ligand (R,R)-10 (see Scheme 1) was prepared
from the reported ethyl bis(2-hydroxyphenyl)phosphinate (16)18
and enantiopure dimethyl-substituted tetraethylene glycol ditosy-
late (S,S)-1819,20 at 50 ꢀC in DMF using K2CO3 as a base. Our research
group showed that the reactions of different phenols with enan-
tiopure secondary tosylates in the presence of K2CO3 using several
dipolar aprotic solvents can lead to some extent of racemization
when carried out at temperatures higher than 50 ꢀC, thus to secure
total inversion of configuration, the reaction temperature was al-
ways kept at or below 50 ꢀC.19–21 Enantiopure macrocycle (R,R)-11
was prepared in a similar manner as described above for obtaining
ligand (R,R)-10 using ditosylate (S,S)-18 and the unreported methyl
bis(2-hydroxyphenyl)phosphinate (17, see Scheme 1).
(R,R)-10 (40%)
1. K2CO3, DMF
(R,R)-11 (14%)
12 (27%)
OQ
2.
R
P
O
R
*
*
13 (34%)
OH
OH
O
OTs
TsO
3
16: Q=Et
(S,S)-18: R=Me
17: Q=Me
19: R=H
1. K2CO3, DMF
2.
16
12 (42%)
O
I
I
O
3
20
X
P
X
OH
Scheme 1. Preparation of novel macrocycles containing the diarylphosphinic acid
alkyl ester moieties.
7: X=Me; 8: X=H; 9: X=Cl
The achiral parent compounds 12 and 13 were obtained from
phosphinates 16 and 17, respectively, using the reported tetra-
ethylene glycol ditosylate (19)19 and applying similar reaction
conditions as in the case of optically active ligands (R,R)-10 and
(R,R)-11 (see Scheme 1). Ligand 12 was also prepared in a better
yield using the reported
ditosylate 19 (see Scheme 1).
Methyl bis(2-hydroxyphenyl)phosphinate (17) was obtained
from the reported diphenyl methyl phosphate (21)23 by applying
the method described for the preparation of phosphinate 1618 with
minor modifications (see Scheme 2).
Enantiopure proton-ionizable ligand (R,R)-14 containing the
diarylphosphinic acid moiety was prepared from the corresponding
phosphinic acid esters (R,R)-10 and (R,R)-11, respectively, by acidic
hydrolysis at elevated temperature using a dioxane–10% aqueous
HCl (1:1) mixture (see Scheme 3). The achiral proton-ionizable
Figure 2. Schematics of diarylphosphinic acids.
O
OQ
P
OH
P
O
a,u
-diiodo-oligoether 2022 instead of
R
O
O
O
O
R
R
O
O
O
O
R
O
O
(R,R)-14: R=Me
15: R=H
(R,R)-10: Q=Et, R=Me
(R,R)-11: Q=Me, R=Me
12: Q=Et, R=H
13: Q=Me, R=H
Figure 3. Schematics of novel enantiopure macrocycles (R,R)-10, (R,R)-11, (R,R)-14 and
achiral parent compounds 12, 13, 15.

P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
10109
significantly from conformer a. It is an intriguing question whether
or not the positive–negative pair of the 1La bands is a consequence
of weaker exciton interaction. Remarkably, the sum of the absolute
band intensities is the lowest in the spectrum in TFE.
OMe
LDA
(THF-hexane)
17 (53%)
O
P
O
O
21
The ECD spectrum of crown ether (R,R)-14 containing the
diarylphosphinic acid unit was measured in MeCN, MeOH, H2O and
TFE [(R,R)-14 is not soluble in iOc]. In MeCN the spectrum features
one strong asymmetric band below 250 nm (Fig. 5), while two
weak bands are present in the 1Lb spectral region. Contrary to this,
five bands appear in MeOH and H2O above 190 nm. The increased
intensity of the negative–positive pair of bands below 210 nm is
compatible with exciton interaction between the 1Bb transitions of
the o-substituted benzene rings. The ECD spectrum in TFE is
dominated by a positive band at 204 nm (D3¼47.8) with a long-
wavelength shoulder and a strong negative band at 192 nm
Scheme 2. Preparation of methyl bis(2-hydroxyphenyl)phosphinate (17).
ligand 15 was obtained from esters 12 and 13, respectively, applying
the same reaction conditions as the ones used in the case of opti-
cally active ligand (R,R)-14 (see Scheme 3).
(R,R)-14 (50%)
(R,R)-14 (55%)
15 (51%)
(R,R)-10
(R,R)-11
12
dioxane-HCl-H2O
(heat)
(
D3¼ꢁ23.5). The 1La bands are rather weak in MeOH and H2O and
15 (53%)
13
are almost absent in TFE. Apparently, the spectra measured in protic
solvents are strongly influenced by high energy electronic transi-
tions. The 1Lb region of the spectra in H2O and MeOH are marked by
a relatively strong positive band near 290 nm with a short-wave-
length shoulder and a weak negative band below 280 nm (Table 1,
Fig. 5, inset). In MeCN the broad negative band is much more in-
tense than the positive one. In TFE only one broad negative band
appears.
The sign and position of the negative couplet in the ECD spectra
of (R,R)-11 in iOc, MeCN and MeOH are the same as those of the
negative couplet in the spectra of (R,R)-14 in MeOH and H2O. This is
a sign of the dominance of basically the same conformation (a) that
is a similar relative position of the benzene rings attached to the
P-atom. MeCN is a nonprotic solvent that stabilizes another confor-
mation of (R,R)-14 (conformer b), TFE only changes the position and
amplitude of the negative couplet of (R,R)-11 while it has a dramatic
spectral effect for (R,R)-14. Titration of the MeCN solution of (R,R)-14
with H2O gives rise to a gradual shift of the spectrum from that
measured in MeCN to the other one observed in H2O. The same
behaviour is seen in the 1Lb region upon water titration (Fig. 6). The
ECD curves have two isodichroic points at 233 nm and w203 nm
strongly suggesting the presence of two conformers: a and b.
In summary, ECD measurements indicated the presence of one
dominant conformer (a) for (R,R)-11 and two conformers (a and b)
and a third species observed only in TFE for (R,R)-14. According
Scheme 3. Preparation of novel proton-ionizable crown ethers containing the diaryl-
phosphinic acid moiety.
2.2. Electronic circular dichroism (ECD) spectroscopy
The ECD spectra of chiral crown ethers (R,R)-10, (R,R)-11 and
(R,R)-14 were studied in solvents of different polarity. In acetoni-
trile (MeCN) the ECD curves of (R,R)-10 and (R,R)-11 overlap in the
190–330 nm spectral range. The ECD spectrum of (R,R)-11 was also
measured in 2,2,2-trifluroethanol (TFE), MeOH and 2,2,4-trime-
thylpentane (isooctane, iOc). Below w250 nm the spectra of (R,R)-
11 in all four solvents are marked by two pairs of oppositely signed
bands (Fig. 4). Two oppositely signed bands are seen also in the 1Lb
spectral region (see the inset of Fig. 4). The positive band shows
a short-wavelength shoulder, which is most separated in iOc and
MeCN.
The intensity of the 1Bb bands below 210 nm is rather high
(Table 1). It fulfils the requirement of exciton interaction. The 1La
bands also appear with increased intensity. The band positions and
intensities of the spectra in iOc, MeCN and MeOH are similar. The
less intense ECD bands of (R,R)-11 in TFE show a definite blue shift
that is likely due to the effect of the strong proton-donating solvent
upon the excitation energies and/or conformation. The similarity of
the ECD spectra of (R,R)-11 in MeCN, MeOH and iOc suggest that the
same conformer (a) dominates the conformational equilibrium in
these solvents and the orientation of the electric transition moment
vectors are rather similar. Based on the same sign pattern of the
ECD bands observed in TFE and the same negative sign of the 1Bb
exciton couplet, the structure of (R,R)-11 in TFE does not differ
to ECD spectroscopic studies, enantiomers of
a-phenylethyl-
ammonium perchlorate (PEA) interact with (R,R)-11 at a 1:1 molar
ratio but do not result in a significant conformational change. In the
presence of (R)- or (S)-PEA the band positions are practically the
same but the amplitudes are smaller than in the spectrum of (R,R)-
11 (not shown). The two ECD curves do not differ significantly. In
short, we cannot speak about enantiomer discrimination.
20
Enantiomers of
a-(1-naphthyl)ethylammonium perchlorate
60
40
(NEA) interact more strongly with (R,R)-11. According to the sum
spectrum, the increased intensity of the band at 223 nm is due to
the negative band of (R)-NEA. The spectral effect of (S)-NEA is less
significant: the bands are less intense and similar to the spectra
measured in the presence of the enantiomers of PEA. This is
a consequence of the positive band of (S)-NEA at 222 nm. The sum
10
0
-10
20
0
260
280
300
/nm
320
spectra (D3sum
the difference spectra (DD3
of enantiomer discrimination (Fig. 7).
¼
D3host
þ
D3NEA) clearly reflect complexing of NEA but
D3exp D3sum) are indicative of the lack
¼
ꢁ
-20
-40
The complexing ability and discriminating power of the phos-
phinic acid (R,R)-14 against the deprotonated form of NEA enan-
tiomers were also probed in MeCN. The ECD spectra (not shown)
clearly show that (R,R)-14 does not bind NEA amines at a 1:1 molar
ratio and does not discriminate between the enantiomers. The
unique ECD spectrum of the phosphinic acid (R,R)-14 in MeCN, the
lack of enantiomer discrimination against PEA and NEA, and its
negligible affinity for deprotonated NEA as well as the result of
190
200
210
220
230
240
250
/nm
Figure 4. Far-UV ECD spectra of (R,R)-11 in MeCN (black), iOc (red), MeOH (green) and
TFE (blue). Inset: near-UV ECD spectra in same solvents.

10110
P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
Table 1
ECD data of (R,R)-10, (R,R)-11 and (R,R)-14
Crown ether compounds
Solvents
lnm (D3)
(R,R)-10
MeCN
200 (62.3)
210 (ꢁ47.2)
224 (ꢁ30.8)
237 (8.6)
(R,R)-11
(R,R)-14
iOc
200 (62.2)
199 (56.4)
199 (55.8)
198 (45.1)
209 (ꢁ40.1)
210 (ꢁ43,5)
210 (ꢁ44.5)
208 (ꢁ32.4)
223 (ꢁ25.9)
223 (ꢁ28.5)
224 (ꢁ28.8)
223 (ꢁ23.8)
236 (12.1)
237 (9.2)
237 (7.1)
236 (5.5)
MeCN
MeOH
TFE
MeCN
H2O
MeOH
TFE
196 (ꢁ5.4)
200 (32.9)
201 (34.6)
204 (47.8)
209 (37.5)
193 (ꢁ11.7)
193 (ꢁ15.5)
192 (ꢁ23.5)
209 (ꢁ32.1)
210 (ꢁ16.9)
213 sh (20.1),
216 sh (15.2)
221 (ꢁ17.8)
225 (ꢁ14.6)
228 (ꢁ1.3)
237 (6.6)
237 (6.2)
Crown ether compounds
Solvents
lnm (D3)
(R,R)-11
iOc
275 (ꢁ2.9)
277 (ꢁ4.7)
280 (ꢁ6.1)
279 (ꢁ5.8)
287 sh (11.4)
288 sh (9.5)
290 sh (10.7)
290 sh (7.6)
293 (18.8)
295 (18.4)
296 (19.5)
296 (13.3)
MeCN
MeOH
TFE
(R,R)-14
MeCN
H2O
MeOH
TFE
277 (ꢁ3.8)
273 (ꢁ2.0)
275 (ꢁ2.1)
279 (ꢁ3.5)
283 (ꢁ3.4)
284 (5.4)
283 (2.0)
282 (ꢁ3.5)
290 (10.3)
291 (7.2)
(a)
60
20
10
0
60
40
20
0
40
20
0
-10
260
280
300
/nm
320
-20
-40
-20
-40
190
200
210
220
/nm
230
240
250
190
200
210
220
/nm
230
240
250
Figure 5. Far-UV ECD spectra of (R,R)-14 in MeCN (black), H2O (red), MeOH (green)
and TFE (blue). Inset: near-UV ECD spectra in same solvents.
(b)
60
40
20
0
20
60
10
0
40
-10
20
0
260
280
300
/nm
320
-20
-40
-20
-40
190
200
210
220
/nm
230
240
250
190
200
210
220
230
240
250
Figure 7. The ECD spectra of (a) (R,R)-10 (black), the heterochiral complex with (S)-
NEA (red) compared to the sum [(D3sum D3host D3NEA), green] and difference
[(DD3 D3exp D3sum), blue] spectra and the spectrum of (S)-NEA (magenta); (b) (R,R)-
10 (black), the homochiral complex with (R)-NEA (red) compared to the sum
[(D3sum D3host D3NEA), green] and difference [(DD3 D3exp D3sum), blue] spectra and
the spectrum of (R)-NEA (magenta).
/nm
¼
þ
¼
ꢁ
Figure 6. ECD spectroscopy monitored water titration of (R,R)-14 starting from 1% v/v
H2O in MeCN to 75% v/v H2O in MeCN. Inset: near-UV spectra in the same solvent
mixture (1% v/v black, 2.5% v/v red, 5% v/v green, 10% v/v blue, 15% v/v pale blue, 20%
v/v magenta, 25% v/v yellow, 35% v/v dark yellow, 50% v/v navy, 75% v/v purple).
¼
þ
¼
ꢁ

P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
10111
(a)
(c)
170
180
190
200
210
180
200
220
240
(b)
(d)
40
20
0
40
20
0
-20
-40
-20
-40
180
200
220
240
180
200
220
240
/nm
/nm
Figure 8. B3LYP/6-311G(d,p) computed ECD spectra of (R,R)-14 (a) monomer and (c) dimer compared with experimental results of (R,R)-14 (b) in H2O and (d) in MeCN.
water titration of the MeCN solution of (R,R)-14 (Fig. 6) prompted
us to consider the possibility of dimerization or aggregation of the
crown ether through the POOH groups. Asfin and co-workers
described the formation of dimers of simple R2POOH molecules
replaced by a strong positive one in MeCN at rcat>1 (rcat¼[cation]/
[crown ether]). ECD titration with Mg2þ ions clearly showed the
formation of a 1:1 complex. Phosphinic acid (R,R)-14 also binds Liþ,
Mg2þ and Zn2þ ions in MeCN. The comparison of the shape of the
ECD spectra of the Mg2þ complexes of (R,R)-10 and (R,R)-14 and
the ECD monitored titration of the crown ethers in MeCN indicate
the formation of 1:1 complexes with basically the same overall
conformation of the macrorings (Fig. 10). It is a question of whether
or not the H-bonds between the POOH groups of the phosphinic
acids are preserved or replaced by an inward position and partici-
pation in cation binding of the POOH groups.
with a strong H-bond (
DH¼24–50 kcal/mol) in the gas phase, low-
temperature argon and N2 matrices, and crystalline films.24 For-
mation of dimers of type R2POOH phosphinic acids (R¼CH3,
CH2Cl, C6H5) was also observed in CCl4 and CH2Cl2 solutions.25 To
support the possible aggregation of the chiral crown ether
phosphinic acid (R,R)-14, theoretical calculations were applied.
Structure optimization was performed at the B3LYP/6-311þG(d,p)
level of theory in the case of both the monomer and the dimer
forms of (R,R)-14. For the calculated conformers, time-dependent
DFT calculations were carried out to receive the ECD spectrum.
The results show similar differences as in the experimental case.
The calculated ECD spectrum of (R,R)-14 monomer is blue shifted
(about 20 nm) but shows the same shape as the measured ECD
spectrum. Calculation was repeated for the dimer form. As shown
in Figure 8, the calculated ECD spectrum does not agree in details
with the one measured in acetonitrile. Nevertheless, the experi-
mental spectrum in acetonitrile does not fit the predicted spec-
trum of the monomer and therefore suggest dimerization or
another form of aggregation.
60
40
20
0
Aggregation of the phosphinic acid-based crown ether (R,R)-14
gives an explanation for its unique ECD spectrum in MeCN and the
lack of the formation of stable complexes with PEA and NEA per-
chlorates and amines. In protic solvents (H2O, MeOH and TFE) the
POOH groups are solvated and cannot fix the dimer or aggregate
form.
-20
-40
-60
190
200
210
220
/nm
230
240
250
Preliminary ECD studies have shown that both the phosphinates
(R,R)-10, (R,R)-11 and the phosphinic acid (R,R)-14 form complexes
with a variety of cations with ionic radii <w1 Å (Liþ, Mg2þ, Zn2þ
,
Figure 9. ECD spectra of (R,R)-10 (black) and its 1:1 complex (rcat¼1) with Mg(ClO4)2
Fig. 9). The strong negative 1Bb couplet of (R,R)-10 and (R,R)-11 is
(red), Li(ClO4) (green) and Zn(ClO4)2 (blue).

10112
P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
interact more strongly with (R,R)-11. The sum spectra clearly reflect
(a)
60
40
20
0
complexing of NEA but the difference spectra are indicative of the
lack of enantiomer discrimination. Ligand (R,R)-14 does also not
discriminate between the enantiomers of NEA and those of the
unprotonated NEA, respectively. This can be explained by aggre-
gation of (R,R)-14. Preliminary ECD studies have shown that ligands
(R,R)-10, (R,R)-11 and (R,R)-14 form complexes with a variety of
cations with ionic radii <w1 Å (e.g., Liþ, Mg2þ, Zn2þ). The strong
negative 1Bb couplet of (R,R)-10 and (R,R)-11 is replaced by a strong
positive one in MeCN at cation to crown ether molar ratios >1. Our
results clearly show the power of ECD spectroscopy in character-
izing the conformations of chiral crown ethers and their complexes.
Detailed UV and ECD titration experiments are in progress to de-
termine the cation selectivity, stoichiometry and stability of cation
complexes of novel ligands (R,R)-10, (R,R)-11, 12, 13, (R,R)-14 and 15.
-20
-40
190
200
210
220
/nm
230
240
250
4. Experimental
4.1. General
(b)
60
40
20
0
Infrared spectra were recorded on a Zeiss Specord IR 75 spec-
trometer. Optical rotations were taken on a Perkin–Elmer 241 po-
larimeter that was calibrated by measuring the optical rotations of
both enantiomers of menthol. 1H (500 MHz, reference: TMS) NMR
spectra were obtained on a Brucker DRX-500 Avance spectrometer.
13C NMR spectra were taken either on a Bruker DRX-500 Avance
spectrometer (125.8 MHz, reference: TMS) or on a Brucker 300
Avance spectrometer (75.5 MHz, reference: TMS) and it is indicated
in each individual case. 13P (121.5 MHz, reference: H3PO4) NMR
spectra were recorded on a Brucker 300 Avance spectrometer. Mass
spectra were recorded on a ZQ 2000 MS instrument (Waters Corp.)
using ESI method. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of Organic Chemis-
try, Institute of Chemistry, L. Eo¨tvo¨s University, Budapest, Hungary.
Melting points were taken on a Boetius micro-melting point ap-
paratus and were uncorrected. Starting materials were purchased
from Aldrich Chemical Company unless otherwise noted. Silica gel
60 F254 (Merck) and aluminium oxide 60 F254 neutral type E (Merck)
plates were used for TLC. Aluminium oxide (neutral, activated,
Brockman I) and silica gel 60 (70–230 mesh, Merck) were used for
column chromatography. Ratios of solvents for the eluents are
given in volumes (mL/mL). Solvents were dried and purified
according to well-established26 methods. Evaporations were car-
ried out under reduced pressure unless otherwise stated.
-20
-40
190
200
210
220
/nm
230
240
250
Figure 10. ECD spectra of (a) (R,R)-10 (black) and Mg(ClO4)2 complexes; (b) (R,R)-14
(black) and Mg(ClO4)2 complexes, rcat¼0.5 (red), rcat¼0.8 (green), rcat¼1 (blue), rcat¼2
(pale blue), rcat¼4 (magenta).
3. Conclusion
The synthesis and characterization of a new type of chiral crown
ethers and their achiral analogues containing an alkyl diaryl-
phosphinate moiety or a diarylphosphinic acid unit have been
achieved. The ECD spectra of the chiral crown ethers (R,R)-10, (R,R)-
11 containing an alkyl diarylphosphinate moiety showed strong
exciton splitting in the 1Bb spectral region of the aromatic chro-
mophores. In the case of the proton-ionizable chiral crown ether
(R,R)-14 containing the phosphinic acid unit the ECD spectrum
measured in MeCN suggested dimerization or aggregation. This
finding was confirmed by theoretical calculation. Contrary to this,
in protic solvents (MeOH, H2O) the ECD spectra showed exciton
interaction of the 1Bb transitions. The sign and position of the
negative 1Bb couplet of (R,R)-11 in iOc, MeCN and MeOH are the
same as those of the negative couplet in the spectra of (R,R)-14 in
MeOH and H2O. This is a sign of the dominance of basically the
same structure (conformer a) that is a similar relative position of
the benzene rings attached to the P-atom. MeCN is a nonprotic
solvent that stabilizes the dimer or aggregate form of (R,R)-14
(conformer b). According to ECD spectroscopic studies, enantio-
Electronic circular dichroism measurements were performed on
a Jasco Dichrograph J-810 at room temperature using 0.02 cm
quartz cell for measurements between 185 and 250 nm and using
0.1 cm between 250 and 330 nm. The spectra were averaged of five
scans. The concentration of crown ethers was 0.5 mM.
Geometry optimizations and the computation of ECD spectra
were performed at the B3LYP/6-311þG(d,p) and B3LYP/6-311G(d,p)
DFT levels with the Gaussian 03 quantum chemical software
package.27
4.2. Synthesis
4.2.1. (6R,16R)-22-Ethoxy-6,16-dimethyl-6,7,9,10,12,13,15,16-
octahydro-22H-22l
5-dibenzo[n,q][1,4,7,10,13,16]pentaoxaphospha-
cyclooctadecin-22-one [(R,R)-10]
Ethyl bis(2-hydroyphenyl)phosphinate (16) (2.1 g, 7.5 mmol),
dimethyl-substituted tertaethylene glycol ditosylate (S,S)-18 (4.0 g,
7.5 mmol) and finely powdered anhydrous K2CO3 (10.4 g,
75.2 mmol) were mixed with vigorous stirring in dry DMF (84 mL)
at rt under Ar. After stirring the reaction mixture at rt for 10 min,
the flask was immersed in an oil bath and the temperature of the
reaction mixture was raised to 50 ꢀC and kept at this temperature
mers of a-phenylethylammonium perchlorate (PEA) interact with
(R,R)-11 at a 1:1 molar ratio. However, the two ECD curves do not
differ significantly, there is no sign of enantiomer discrimination.
Enantiomers of a-(1-naphthyl)ethylammonium perchlorate (NEA)

P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
10113
with vigorous stirring until TLC analysis showed the total con-
4.2.3. 22-Ethoxy-6,7,9,10,12,13,15,16-octahydro-22H-22l5
-
sumption of the starting ditosylate (S,S)-18 (20 days). The solvent
was removed at 40 ꢀC and the residue was taken up in a mixture of
ice-water (160 mL) and CH2Cl2 (200 mL). The aqueous phase was
extracted with CH2Cl2 (3ꢂ60 mL). The combined organic phase was
shaken with water (200 mL), dried over MgSO4, filtered and the
solvent was removed. The crude product was purified by chroma-
tography first on aluminium oxide using EtOH–toluene (1:80)
mixture as an eluent followed by chromatography on silica gel
using MeOH–CH2Cl2 (1:40) mixture as an eluent. The white solid
was recrystallized from hot hexane to give (R,R)-10 (1.41 g, 40%) as
white needles. Mp: 111–112 ꢀC (hexane). Rf: 0.25 (aluminium oxide
dibenzo[n,q][1,4,7,10,13,16]pentaoxaphosphacyclooctadecin-
22-one (12)
4.2.3.1. Starting from ditosylate 19. Achiral ligand 12 was prepared
as described above for its optically active analogue (R,R)-10 starting
from ethyl bis(2-hydrosyphenyl)phosphinate (16) (0.50 g,
1.8 mmol), ditosylate 19 (0.19 g, 1.8 mmol), finely powdered anhy-
drous K2CO3 (2.5 g 18 mmol) and pure DMF (21 mL). White prisms.
Yield: 0.21 g (27%). Mp: 88–89 ꢀC (isopropyl ether). Rf: 0.20 (alu-
minium oxide TLC, EtOH-toluene 1:40), Rf: 0.10 (silica gel TLC,
MeOH/CH2Cl2 1:40); IR (KBr) nmax 3048, 2960, 2880, 1592, 1576,
1544, 1480, 1448, 1352, 1280, 1232, 1212, 1132, 1104, 1040, 944, 760,
TLC, EtOH–toluene 1:40), Rf: 0.14 (silica gel TLC, MeOH–CH2Cl2
25
1:40); [
a]
ꢁ3.13 (c 3.8, CH2Cl2); IR (KBr) nmax 3064, 3040, 2976,
544 cmꢁ1; 1H NMR (CDCl3)
3.76–3.89 (m, 4H), 4.05–4.17 (m, 6H), 6.98–7.05 (m, 4H), 7.43–7.46
(m, 2H), 7.94–7.99 (m, 2H); 13C NMR (125.8 MHz, CDCl3)
16.48 (d,
d
1.32 (t, J¼7 Hz, 3H), 3.20–3.30 (m, 8H),
D
2952, 2936, 2912, 2896, 1696, 1592, 1476, 1448, 1380, 1288, 1264,
1244, 1224, 1208, 1144, 1128, 1116, 1080, 1072, 1032, 984, 928, 872,
d
792, 760, 712, 608, 552 cmꢁ1; 1H NMR (CDCl3)
d
1.17 (d, J¼7 Hz, 3H),
J¼6.06 Hz, CH3), 60.38 (d, J¼6.06 Hz, ethyl CH2O), 67.19 (s, OCH2),
69.87 (s, OCH2), 70.75 (s, OCH2), 71.35 (s, OCH2), 112.08 (d,
J¼7.27 Hz, ArC3), 120.12 (d, J¼12.11 Hz, ArC5), 121.13 (d, J¼141.69 Hz,
ArC1 next to P atom), 133.07 (s, ArC4), 134.37 (d, J¼6.06 Hz, ArC6),
1.26 (d, J¼7 Hz, 3H), 1.39 (t, J¼7 Hz, 3H), 2.76–2.79 (m, 2H), 2.89–
2.92 (m, 2H), 2.93–3.06 (m, 2H), 3.29–3.40 (m, 6H), 3.86–3.88 (m,
1H), 4.16–4.18 (m, 1H), 4.51–4.55 (m, 2H), 6.94–7.06 (m, 4H), 7.45–
7.54 (m, 2H), 7.91–7.94 (m, 1H), 8.19–8.22 (m, 1H); 13C NMR
160.22 (d, J¼4.84 Hz, ArC2 next to O atom); 31P (CDCl3)
d 27.08; MS:
(75.5 MHz, CDCl3)
d
16.65 (d, J¼6.82 Hz, ethyl CH3), 17.42 and 17.56
437 (Mþ1)þ. Anal. Calcd for C22H29O7P: C, 60.54; H, 6.70; P, 7.10.
(s, diastereotopic CH3 groups attached to the macroring), 60.18 (d,
J¼5.58 Hz, ethyl CH2O), 71.08 and 71.12 (s, diastereotopic OCH2
groups), 71.20 and 71.32 (s, diastereotopic OCH2 groups), 72.50 and
73.38 (s, diastereotopic OCH2 groups), 74.52 and 74.58 (s, diastereo-
topic OCH groups), 112.34 and 113.14 (d, J¼7.44 and 8.68 Hz,
diastereotopic ArC3), 119.95 (d, J¼12.41 Hz, ArC5), 121.10 and 122.67
(d, J¼134.60 and 150.11 Hz, diastereotropic ArC1 next to P atom),
132.89 and 136.43 (d, J¼1.86 and 6.82 Hz, diastereotopic ArC6),
133.40 and 133.46 (s, diastereotopic ArC4), 159.32 and 160.19 (d,
J¼3.72 and 5.58 Hz, diastereotopic ArC2 next to O atom); 31P (CDCl3)
Found: C, 60.54; H, 6.53; P, 6.86.
4.2.3.2. Starting from
obtained starting from ethyl bis(2-hydrosyphenyl)phosphinate (16)
(0.50 g, 1.8 mmol), -diiodo-oligoether 20 (0.75 g, 1.8 mmol),
a,u-diiodo-oligoether 20. Ligand 12 was also
a,u
finely powdered anhydrous K2CO3 (2.5 g 18 mmol) and pure DMF
(21 mL). Yield: 0.33 g (42%). Macrocycle 12 obtained this way was
identical in every respect to that prepared by the previous
procedure.
d
25.25; MS: 465 (Mþ1)þ. Anal. Calcd for C24H33O7P: C, 62.06; H,
4.2.4. 22-Methoxy-6,7,9,10,12,13,15,16-octahydro-22H-22l5
-
dibenzo[n,q][1,4,7,10,13,16]pentaoxaphosphacyclooctadecin-
22-one (13)
7.16; P, 6.67. Found: C, 62.04; H, 7.20; P, 6.46.
4.2.2. (6R,16R)-22-Methoxy-6,16-dimethyl-6,7,9,10,12,13,15,16-
Achiral macrocycle 13 was prepared as described above for its
optically active analogue (R,R)-10 starting from methyl bis(2-
hydrosyphenyl)phosphinate (17) (0.50 g, 1.9 mmol), ditosylate 19
(0.95 g, 1.9 mmol), finely powdered anhydrous K2CO3 (2.64 g,
19 mmol) and pure DMF (22 mL). White prisms. Yield: 0.27 g (34%).
Mp: 117–118 ꢀC (isopropyl ether). Rf: 0.20 (aluminium oxide TLC,
EtOH–toluene 1:40), Rf: 0.10 (silica gel TLC, MeOH–CH2Cl2 1:40); IR
(KBr) nmax 3064, 3040, 2964, 2872, 1592, 1536, 1472, 1460, 1448,
1352,1292,1280,1256,1248,1224,1216,1208,1132,1120,1104,1064,
1040, 992, 932, 888, 824, 796, 764, 712, 568, 488, 448 cmꢁ1; 1H NMR
octahydro-22H-22l
5-dibenzo[n,q][1,4,7,10,13,16]penta-
oxaphosphacyclooctadecin-22-one [(R,R)-11]
Optically active ligand (R,R)-11 was prepared in the same way as
described above for its analogue (R,R)-10 starting from methyl
bis(2-hydroxyphenyl)phosphinate (17) (0.50 g, 1.9 mmol), ditosy-
late (S,S)-18 (1.0 g, 1.9 mmol), finely powdered anhydrous K2CO3
(2.63 g, 19 mmol) and pure DMF (22 mL). White needles. Yield:
0.12 g (14%). Mp: 127–128 ꢀC (hexane). Rf: 0.25 (aluminium oxide
TLC, EtOH–toluene 1:40), Rf: 0.14 (silica gel TLC, MeOH–CH2Cl2
25
1:40); [
a
]
ꢁ21.4 (c 1.0, CH2Cl2); IR (KBr) nmax 3120, 3056, 3040,
(CDCl3)
4.09–4.16 (m, 4H), 6.97–7.04 (m, 4H), 7.43–7.46 (m, 2H), 7.89–7.94
(m, 2H); 13C NMR (75.5 MHz, CDCl3)
d 3.22–3.30 (m, 8H), 3.36–3.43 (m, 4H), 3.72–3.74 (m, 3H),
D
2974, 2948, 2910, 2872, 1592, 1480, 1460, 1448, 1376, 1288, 1264,
1248, 1232, 1216, 1144, 1120, 1104, 1028, 960, 884, 792, 768, 568,
d
51.53 (d, J¼5.58 Hz, OCH3),
552, 516 cmꢁ1
;
1H NMR (CDCl3)
d
1.11 (d, J¼6.5 Hz, 3H), 1.15 (d,
67.56 (s, OCH2), 70.04 (s, OCH2), 70.98 (s, OCH2), 71.54 (s, OCH2),
112.31 (d, J¼7.44 Hz, ArC3), 120.42 (d, J¼13.65 Hz, ArC5), 120.72 (d,
J¼141.42 Hz, ArC1 next to P atom),133.51 (d, J¼1.86 Hz, ArC4),134.61
(d, J¼6.82, ArC6), 160.47 (d, J¼4.34 Hz, ArC2 next to O atom); 31P
J¼6.5 Hz, 3H), 2.75–2.79 (m, 2H), 2.90–2.96 (m, 2H), 3.01–3.07 (m,
3
2H), 3.29–3.40 (m, 6H), 3.68 (d, j JjP–H(Me)¼11 Hz, 3H), 4.50–4.57
(m, 2H), 6.95–7.06 (m, 4H), 7.36–7.45 (m, 2H), 7.84–7.87 (m, 1H),
8.11–8.14 (m, 1H); 13C NMR (75.5 MHz, CDCl3)
d
17.43 and 17.47 (s,
(CDCl3)
d
30.07; MS: 423 (Mþ1)þ. Anal. Calcd for C21H27O7P: C,
diastereotopic CH3 groups attached to the macroring), 50.96 (d,
J¼6.20 Hz, OCH3), 71.07 and 71.12 (s, diastereotopic OCH2 groups),
71.23 and 71.27 (s, diastereotopic OCH2 groups), 72.73 and 73.33 (s,
diastereotopic OCH2 groups), 74.49 and 74.54 (s, diastereotopic
OCH2 groups), 112.49 and 113.18 (d, J¼7.44 and 8.06 Hz, diastereo-
topic ArC3), 120.00 and 120.05 (d, J¼11.79 and 12.41 Hz, diaster-
eotopic ArC5), 120.34 and 122.34 (d, J¼134.60 and 150.11 Hz,
diastereotopic ArC1 next to P atom), 133.00 and 133.57 (d, J¼1.24
and 1.86 Hz, diastereotopic ArC4), 133.29 and 136.54 (d, J¼3.72 and
7.44 Hz, diastereotopic ArC6), 159.34 and 160.17 (d, J¼3.72 and
59.71; H, 6.44; P, 7.33. Found: C, 59.56; H, 6.43; P, 7.06.
4.2.5. (6R,16R)-22-Hydroxy-6,16-dimethyl-6,7,9,10,12,13,15,16-
octahydro-22H-22l
5-dibenzo[n,q][1,4,7,10,13,16]pentaoxaphospha-
cyclooctadecin-22-one [(R,R)-14]
4.2.5.1. Starting from ethyl ester (R,R)-10. To a vigorously stirred
solution of optically active macrocycle containing the ethyl diaryl-
phosphinate moiety [(R,R)-10] (288 mg, 0.62 mmol) in freshly
distilled dioxane (18 mL) was added 10% (w/w) aqueous HCl solu-
tion (18 mL) at rt. The flask was immersed in an oil bath and the
temperature of the reaction mixture was raised to 80 ꢀC and kept at
this temperature with vigorous stirring until TLC analysis showed
5.58 Hz, diastereotopic ArC2 next to O atom); 31P (CDCl3)
d 27.69;
MS: 451 (Mþ1)þ. Anal. Calcd for C23H31O7P: C, 61.33; H, 6.94; P, 6.88.
Found: C, 61.12; H, 6.74; P, 6.86.

10114
P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
the total consumption of the starting material (60 h). After the re-
action was completed, the volatile components were removed by
distillation at 30 ꢀC. The residue was taken up in freshly distilled
dioxane (12 mL) and the solvent was removed. The latter procedure
was repeated and the crude product was dried over KOH pellets
under reduced pressure. The white solid material was recrystallized
from boiling water using charcoal to give pure (R,R)-14 (136 mg,
The resulting reaction mixture was stirred at ꢁ75 ꢀC for another
60 min, then it was allowed to warm up to rt and it was stirred at rt
for 4 h. After the reaction was completed, the mixture was added in
small portions to a vigorously stirred mixture of CH2Cl2 (600 mL),
saturated aqueous NH4Cl solution (470 mL) and ice (200 g). The
organic phase was separated and the aqueous one was extracted
with CH2Cl2 (2ꢂ200 mL). The combined organic phase was shaken
with water (500 mL), dried over MgSO4, filtered and the solvent
was removed. The crude product was first purified by chromatog-
raphy on silica gel using an acetone–toluene 1:20 mixture as eluent
then by recrystallization from toluene to give pure 17 as white
prisms. Yield: 8.75 g (53%). Mp: 146–147 ꢀC (toluene). Rf: 0.20
(silica gel TLC, acetone–toluene 1:20); IR (KBr) nmax 3430, 3235,
3064, 2960, 2858, 1616, 1608, 1576, 1464, 1456, 1448, 1412, 1372,
1304,1240,1184,1172,1140,1128,1120,1100,1088,1080,1072,1060,
50%) as white prisms. Mp: 181–182 ꢀC (water). Rf: 0.26 (silica gel
25
TLC, MeOH–ClCH2CH2Cl 1:4); [
a
]
D
ꢁ100.74 (c 1.35, CH2Cl2); IR
(KBr) nmax 3448, 3064, 3048, 2976, 2968, 2936, 2312, 1659, 1592,
1578, 1476, 1460, 1444, 1412, 1380, 1355, 1280, 1244, 1140, 1112,
1092, 1024, 1008, 992, 976, 940, 804, 756, 708, 608, 560, 512 cmꢁ1
;
1H NMR (CDCl3þD2O)
1.17 (d, J¼6 Hz, 6H), 3.13–3.16 (m, 2H), 3.27–
d
3.31 (m, 2H), 3.34–3.38 (m, 2H), 3.43–3.47 (m, 2H), 3.51–3.54 (m,
2H), 3.58–3.62 (m, 2H), 4.56–4.59 (m, 2H), 6.93–6.96 (m, 4H), 7.40–
7.43 (m, 2H), 7.75–7.80 (m, 2H); 13C NMR (125.8 MHz, CDCl3)
d
17.31
1036, 952, 840, 808, 756, 732, 704, 688, 584, 548, 524, 488 cmꢁ1; 1H
3
(s, CH3), 70.97 (s, OCH2), 71.23 (s, OCH2), 73.23 (s, OCH2), 74.36 (s,
OCH), 112.66 (d, J¼7.27 Hz, ArC3), 120.06 (d, J¼14.53 Hz, ArC5),
123.02 (d, J¼144.11 Hz, ArC1 next to P atom), 132.99 (s, ArC4), 134.34
NMR (CDCl3)
d
3.84 (d, j JjP–H(Me)¼12 Hz, 3H), 6.94–7.00 (m, 4H),
7.43–7.48 (m, 4H), 9.92 (br s, 2H); 13C NMR (75.5 MHz, CDCl3)
d
52.50 (d, J¼6.82 Hz, OCH3), 111.03 (d, J¼137.70 Hz, ArC1 next to P
(d, J¼6.06 Hz, ArC6), 159.52 (d, J¼3.63 Hz, ArC2 next to O atom); 31
P
atom), 118.63 (d, J¼9.92 Hz, ArC3), 120.17 (d, J¼13.02 Hz, ArC5),
131.67 (d, J¼8.07 Hz, ArC6), 135.66 (d, J¼2.48 Hz, ArC4), 162.34 (d,
(CDCl3)
d
13.95; MS: 437 (Mþ1)þ. Anal. Calcd for C22H29O7P: C,
60.54; H, 6.70; P, 7.10. Found: C, 60.43; H, 6.60; P, 7.10.
J¼5.59 Hz, ArC2 next to O atom); 31P (CDCl3)
d 45.86; MS: 265
(Mþ1)þ. Anal. Calcd for C13H13O4P: C, 59.10; H, 4.96; P,11.72. Found:
4.2.5.2. Starting from methyl ester (R,R)-11. Proton-ionizable macro-
cycle (R,R)-14 was also obtained starting from methyl ester (R,R)-11
(279 mg, 0.62 mmol) and following the procedure described above
for the acid hydrolysis of ethyl ester (R,R)-10. Yield: 149 mg (55%).
Ligand (R,R)-14 obtained this way was identical in every respect to
that prepared by the previous procedure.
C, 59.27; H, 4.79; P, 11.64.
Acknowledgements
This work was supported by the Hungarian Scientific Research
Fund (OTKA K62654 to P.H., PD71817 to V.F., PD71910 to T.T. and
T49792, NI68466 to M.H.), GVOP-3.2.1-2004-04-0345/3,0 and by
the Ministry of Education of Hungary (Postdoctoral Fellowship PAL
11/2003 to T.T.). The HPC Group computer facility, University of
Szeged was used for several computations. The authors would like
4.2.6. 22-Hydroxy-6,7,9,10,12,13,15,16-octahydro-22H-22l5
-
dibenzo[n,q][1,4,7,10,13,16]pentaoxaphosphacyclooctadecin-
22-one (15)
´
to thank Dr. Elemer Vass for helpful discussion.
4.2.6.1. Starting from ethyl ester 12. Achiral macrocycle 15 was
prepared as described above for its optically active analogue (R,R)-
14 starting from ethyl ester 12 (271 mg, 0.62 mmol). White prisms.
Yield: 128 mg (51%). Mp: 170–171 ꢀC (water). Rf: 0.14 (silica gel TLC,
MeOH–ClCH2CH2Cl 1:4); IR (KBr) nmax 3424, 3136, 3080, 3056,
2960, 2944, 2864, 2048, 1658, 1592, 1576, 1476, 1444, 1352, 1304,
1276, 1264, 1216, 1204, 1144, 1136, 1128, 1112, 1104, 1080, 1032, 968,
References and notes
1. McDaniel, C. W.; Bradshaw, J. S.; Izatt, R. M. Heterocycles 1990, 30, 665–706.
2. Bartsch, R. A. ACS Symposium Series 1999, 716, 146–155; Chem. Abstr. 1999, 130,
201386.
3. Bradshaw, J. S.; Izatt, R. M.; Huszthy, P.; Nakatsuji, Y.; Biernat, J. F.; Koyama, H.;
McDaniel, C. W.; Wood, S. A.; Nielsen, R. B.; LindH, G. C.; Bruening, R. L.; Lamb,
J. D.; Christensen, J. J. Studies Org. Chem. 1987, 31, 553–560.
4. Huszthy, P.; Kertesz, J.; Bradshaw, J. S.; Izatt, R. M.; Redd, J. T. J. Heterocycl. Chem.
2001, 38, 1259–1264.
5. Huszthy, P.; Vermes, B.; Bathori, N.; Czugler, M. Tetrahedron 2003, 59, 9371–
942, 800, 760, 704, 552, 516, 496, 480, 436 cmꢁ1
(CDCl3þD2O) 3.63–3.72 (m, 12H), 4.18–4.22 (m, 4 m), 6.91–7.01
(m, 4H), 7.45–7.49 (m, 2H), 7.59–7.63 (m, 2H); 13C NMR (75.5 MHz,
CDCl3) 68.46 (s, OCH2), 69.43 (s, OCH2), 70.44 (s, OCH2), 71.47 (s,
;
1H NMR
d
´
´
d
9377.
OCH2), 112.23 (d, J¼6.82 Hz, ArC3), 121.03 (d, J¼13.03 Hz, ArC5),
121.95 (d, J¼138.32 Hz, ArC1 next to P atom), 133.56 (d, J¼1.24 Hz,
ArC4), 134.31 (d, J¼9.92 Hz, ArC6), 160.12 (d, J¼1.86 Hz, ArC2 next to
6. Kova´cs, I.; Huszthy, P.; Bertha, F.; Sziebert, D. Tetrahedron: Asymmetry 2006, 17,
2538–2547.
7. Bradshaw, J. S.; Huszthy, P.; Izatt, R. M. J. Heterocycl. Chem. 1986, 23, 1673–1676.
8. Izatt, R. M.; LindH, G. C.; Huszthy, P.; Clark, G. A.; Bruening, R. L.; Bradshaw, J. S.;
Christensen, J. J. J. Inclusion Phenom. Mol. Recognit. Chem. 1989, 7, 501–509.
9. Gokel, G. W.; Nakano, A. In Crown Compounds: Toward Future Application;
Cooper, S. R., Ed.; VCH: New York, NY, 1992; Chapter 1.
10. Tsukube, H.; Yamada, T.; Shinoda, S. Ind. Eng. Chem. Res. 2000, 39, 3412–3418.
11. Erickson, S. D.; Still, W. C. Tetrahedron Lett. 1990, 31, 4253–4256.
12. Sasaki, S.; Naito, H.; Maruta, K.; Kawahara, E.; Maeda, M. Tetrahedron Lett. 1994,
35, 3337–3340.
13. Shibutani, Y.; Mino, S.; Long, S. S.; Moriuchi-Kawakami, T.; Yakabe, K.; Shono, T.
Chem. Lett. 1997, 26, 49–50.
14. Mastryukova, T. A.; Melenteva, T. A.; Shipov, A. E.; Kobashnik, M. I. Zh. Obshch.
Khim. 1959, 29, 2178–2182; Chem. Abstr. 1960, 54, 10463g.
15. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Chem. Rev. 1995, 95,
2529–2586.
O atom); 31P (CDCl3)
d
27.43; MS: 409 (Mþ1)þ. Anal. Calcd for
C
20H25O7P: C, 58.82; H, 6.17; P, 7.58. Found: C, 58.74; H, 6.20; P, 7.47.
4.2.6.2. Starting from methyl ester 13. Proton-ionizable macrocycle
15 was also obtained starting from methyl ester 13 (262 mg,
0.62 mmol) and following the procedure described above for the
acid hydrolysis of ethyl ester (R,R)-10. Yield: 133 mg (53%). Ligand
15 obtained this way was identical in every respect to that prepared
by the previous procedure.
4.2.7. Methyl bis(2-hydroxyphenyl)phosphinate (17)
16. Lehn, J. M. Supramolecular Chemistry; VCH: Weinheim, Germany, 1995.
17. Farkas, V.; Szalay, L.; Vass, E.; Hollo´si, M.; Horva´th, G.; Huszthy, P. Chirality 2003,
15, S65–S73.
18. Dhawan, B.; Redmore, D. J. Org. Chem. 1986, 51, 179–183.
19. Huszthy, P.; Samu, E.; Vermes, B.; Mezey-Va´ndor, G.; No´gra´di, M.; Bradshaw,
J. S.; Izatt, R. M. Tetrahedron 1999, 55, 1491–1504.
To a vigorously stirred solution of freshly distilled pure and dry
diisopropylamine (35 mL, 25.3 g, 0.25 mol) in pure and dry THF
(78 mL) was added 2.5 M n-butyllithium solution in hexanes
(100 mL, 0.25 mol) at ꢁ75 ꢀC under Ar in 30 min and stirring was
continued another 30 min at ꢁ75 ꢀC. After the LDA solution was
formed, diphenyl methyl phosphate (21) (16.53 g, 62.6 mmol) dis-
solved in pure and dry THF (78 mL) was added in 60 min at ꢁ75 ꢀC.
20. Samu, E.; Huszthy, P.; Somogyi, L.; Hollosi, M. Tetrahedron: Asymmetry 1999, 10,
2775–2795.
´
21. Lakatos, S.; Fetter, J.; Bertha, F.; Huszthy, P.; Toth, T.; Farkas, V.; Orosz, G.;
Hollo´si, M. Tetrahedron 2008, 64, 1012–1022.

P. Huszthy et al. / Tetrahedron 64 (2008) 10107–10115
10115
22. Marquis, D.; Desvergne, J. P.; Bouas-Laurent, H. J. Org. Chem. 1995, 60, 7984–
7996.
23. Gupta, A. K.; Acharya, J.; Dubey, D. K.; Kaushik, M. P. Synth. Commun. 2007, 37,
3403–3407.
24. Asfin, R. E.; Denisov, G. S.; Mielke, Z.; Tokhadze, K. G. Opt. Spectrosc. 2005,
99, 56–67.
25. Asfin, R. E.; Denisov, G. S.; Tokhadze, K. G. J. Mol. Struct. 2006, 790, 11–17.
26. Riddick, J. A.; Burger, W. B. In Techniques of Organic Chemistry, 3rd ed.; Weiss-
berger, A., Ed.; Wiley-Interscience: New York, NY, 1970; Vol. II.
27. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
¨
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, R.C;
Gaussian,: Wallingford, CT, 2004.