Synthesis of new optically active pyridino- and pyridono-18-crown-6 type ligands containing four lipophilic chains

Article abstract of DOI:10.1016/S0957-4166(03)00590-1

Highly lipophilic enantiomerically pure pyridino- and pyridono-18-crown-6 type ligands containing four stereogenic centers to which butyl or butoxymethyl groups are attached have been synthesized. X-Ray analysis of the (R)-1-phenylethylammonium and benzyl

Full text of DOI:10.1016/S0957-4166(03)00590-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2803–2811
Synthesis of new optically active pyridino- and
pyridono-18-crown-6 type ligands containing four lipophilic
chains
Ja´nos Gerencse´r,a Nikoletta Ba´thori,b Ma´tya´s Czugler,b Pe´ter Huszthyc,* and Miha´ly No´gra´dic
aComGenex Inc., Budapest, Hungary PO Box 73, H-1388 Budapest 62, Hungary
bInstitute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525, Budapest, POB 17, Hungary
cInstitute for Organic Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, POB. 91, Hungary
Received 2 July 2003; accepted 22 July 2003
Abstract—Highly lipophilic enantiomerically pure pyridino- and pyridono-18-crown-6 type ligands containing four stereogenic
centers to which butyl or butoxymethyl groups are attached have been synthesized. X-Ray analysis of the (R)-1-phenylethylam-
monium and benzylammonium perchlorate complexes of the unsubstituted pyridono ligand revealed, that, in contrast to the free
ligand, in the complex the hydroxypyridine tautomer is present.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
3 and (S,S)-4 have been thoroughly studied,5,6 to our
knowledge only one enantiomerically pure analogue
containing four alkyl substituents (R,R,R,R)-4 (Fig. 1)
has been reported.7 The latter ligand showed high
enantioselectivity towards the enantiomers of 1-(1-
naphthyl)ethylammonium perchlorate (NEA) and espe-
cially to 1-phenylethylammonium perchlorate (PEA)
expressed as the differences of the free energies of
activation for the dissociation of diastereomeric com-
plexes (R,R,R,R)-4–(S)-NEA and (R,R,R,R)-4–(R)-
NEA (DDGcc 0.9 kcal/mol) and (R,R,R,R)-4–(S)-PEA
and (R,R,R,R)-4–(R)-PEA (DDGcc 2.2 kcal/mol)
respectively. DDGcc values were obtained using temper-
ature dependent 1H NMR experiments.7 Ligand
(R,R,R,R)-4, however, is not lipophilic enough for
studying the enantioselective transport of chiral organic
ammonium salts or the selective transport of metal ions
in an aqueous source phase/organic membrane/aqueous
receiving phase system8 or for potentiometric sensing
when incorporated into an electrode membrane.3,9–11
For the above studies more lipophilic ligands than
(R,R,R,R)-4 are required. Lipophilic pyridino ligands
containing substituents both at the pyridine ring in
p-position, e.g. 5,12 or also at the macroring, e.g. ( )-
6,12 (S,S)-713 (S,S)-8 and (R,R)-914 were also prepared.
Unfortunately none of them was suitable for any of the
intended applications, because they were very sensitive
to acid and were immediately transformed into the
stable pyridono ligands 10,12 ( )-11,12 (S,S)-1213, (S,S)-
Since the report of Bradshaw et al. on the first optically
active pyridino-18-crown-6 type ligand (S,S)-1 (Fig. 1)
20 years ago1 several dozen similar macrocycles con-
taining two stereogenic centers on the macroring have
been prepared and studied for enantiomeric recognition
of chiral protonated primary arylalkyl amines.2–5 These
studies have shown that the degree of enantiomeric
recognition (enantioselectivity) is governed by the bal-
ance of intermolecular attractive and repulsive interac-
tions. Probably the most important attractive
interaction is the tripod-like H-bonding between the
three ammonium hydrogens of the guest and the pyri-
dine nitrogen and two alternate oxygen atoms of the
host, respectively. Frequently,6 but not necessarily, p–p
stacking between the aromatic rings of the host and
guest is added to this attractive interaction. The third
and crucial interaction is the steric repulsion between
the substituents at the stereogenic centers of the macro-
cycle and certain hydrogen atoms of the alkyl or ary-
lalkyl ammonium salt.5
Although the enantiomerically pure pyridino macrocy-
cles containing two substituents, such as (S,S)-2, (R,R)-
* Corresponding author. Tel.: +36-1-463-2111; fax: +36-1-463-3297;
e-mail: huszthy@mail.bme.hu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00590-1

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J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
Figure 1. Reported pyridino-, p-substituted-pyridino-, and pyridono-18-crown-6 type ligands relevant to the present work.
1314 and (R,R)-1414 by removal of the tetra-
applications. The latter pyridono macrocycles were
used in the preparation of such substituted pyridino
hosts which were attached to different solid supports
for enantioseparation of racemic primary organic
ammonium salts.13,14 To our knowledge no optically
active pyridono-18-crown-6 type ligand containing four
stereogenic centers has been reported to date. Note that
natural ionophores, such as valinomycin, lasalocid,
monensin, etc. also contain several stereogenic centers
and use their chirality for the selective transport of
metal ions through biological membranes.17,18 Several
studies have shown that the stereostructure of chiral
synthetic ligands has also a great influence on binding,
solvent extraction and transport of metal ions.18–21
hydropyranyl group.
Among the pyridono macrocycles the most lipophilic
one i.e. ( )-11 was studied thoroughly. It turned out to
be a good carrier for Ag+ and Pb2+ ions showing some
selectivity for Pb2+ when applying a neutral source
phase,15 and in the case of a source phase pH higher
than 12, the ligand transported K+ very selectively over
other alkali metal cations15,16 in a water–CH2Cl2–water
liquid membrane system.
Our recent results presented herein confirm that pyri-
dono-18-crown-6 type macrocycles can also form stable
complexes with primary alkyl or arylalkyl ammonium
salts.
In our search for enantiopure highly lipophilic chiral
hosts with enhanced selectivity both for metal ions and
the enantiomers of chiral guests in binding, solvent
extraction, membrane transport and potentiometric
studies, we prepared ligands (R,R,R,R)-15–(S,S,S,S)-20
(see Fig. 2). In ligands (R,R,R,R)-16 and (S,S,S,S)-18
the benzyloxy group proved to be quite stable under
mildly acidic and basic conditions. The benzyloxy
group also increases lipophilicity, so these ligands not
only serve as precursors for the pyridono analogues
(R,R,R,R)-19 and (S,S,S,S)-20, but are also excellent
candidates for the above mentioned applications.
In order to get a deeper insight into the nature of
selective complexation, crystals amenable to X-ray
analysis were prepared from the complexes of (R)-1-
phenylethylammonium and benzylammonium perchlo-
rates [(R)-PEA and BA] of the unsubstituted achiral
pyridono ligand 10. An interesting result of this study
was that in the complexes the ligand was in the hydroxy-
pyridine form, in contrast to the free ligand which was
shown to be in the tautomeric pyridone form.12 Thus,
similar to pyridino type ligands host and guest were
held together by strong multipod-like hydrogen bond-
ing.5–7 Tautomerization during complexation was also
confirmed by IR and NMR spectroscopy.
2. Results and discussion
Thus, chiral lipophilic pyridono-18-crown-6 type lig-
ands can also be good candidates as carriers for enan-
tioselective transport in a water–CH2Cl2–water system,
for enantioselective solvent extraction and for enan-
tioselective potentiometric sensors of chiral primary
ammonium salts. Ligands (S,S)-12, (S,S)-13 and (R,R)-
14, however, are not lipophilic enough for the above
Novel chiral pyridino-18-crown-6 type ligands
(R,R,R,R)-15,
(R,R,R,R)-16,
(S,S,S,S)-17
and
(S,S,S,S)-18 (Fig. 2) were prepared by the treatment of
the new chiral tetraethylene glycols (R,R,R,R)-21 and
(S,S,S,S)-22 with the corresponding pyridine-2,6-
dimethanol ditosylates 2322 and 2422 in the presence of
sodium hydride as a base (Scheme 1).

J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
2805
Figure 2. Novel optically active pyridino- and pyridono-18-crown-6 type ligands containing four lipophilic chains.
Scheme 1. Preparation of novel chiral pyridino-18-crown-6 type macrocycles.
New chiral pyridono-18-crown-6 type macrocycles
(R,R,R,R)-19 and (S,S,S,S)-20 were obtained by
removal of the benzyl group from benzyloxypyridino-18-
crown-6 ligands (R,R,R,R)-16 and (S,S,S,S)-18 by cata-
lytic hydrogenation (Scheme 2).
ether (R,R)-27. Reaction of (R,R)-27 with diethylene
glycol di-p-tosylate 28 in a 2:1 molar ratio followed by
debenzylation of the resulting oligoether (R,R,R,R)-29
gave the tetraethylene glycol (R,R,R,R)-21 (Scheme 3).
The tetrabutoxymethyl-substituted tetraethylene glycol
(S,S,S,S)-22, our key intermediate needed for obtaining
chiral ligands (S,S,S,S)-17 and (S,S,S,S)-18, was pre-
pared from the reported (S,S)-2,3-benzylidene-threitol
(S,S)-30.25 The disodium salt of diol (S,S)-30 was reacted
with butyl bromide and then the benzylidene acetal
(S,S)-31 was cleaved with DIBALH.24 The sodium salt
of monobenzyl ether (S,S)-32 was reacted with 0.5 equiv.
of diethylene glycol di-p-tosylate 28 followed by the
removal of the benzyl groups from (S,S,S,S)-33 by
catalytic hydrogenation to give (S,S,S.S)-22 (Scheme 4).
Scheme 2. Preparation of novel chiral pyridono-18-crown-6
type macrocycles.
Chiral tetraethylene glycol derivative (R,R,R,R)-21 was
prepared starting from (R,R)-decane-5,6-diol (R,R)-25,23
which was transformed to its benzylidene acetal (R,R)-26
followed by selective cleavage with diisobutyl-
aluminum hydride (DIBALH)24 to give the monobenzyl
In order to obtain more information about the forces
operating in the complexation, crystals amenable for
Scheme 3. Preparation of new chiral tetrabutyl-substituted tetraethylene glycol.

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J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
Scheme 4. Preparation of new chiral tetrabutoxymethyl-substituted tetraethylene glycol.
X-ray analysis were prepared from the (R)-1-phenylethyl-
ammonium [(R)-PEA] and benzylammonium (BA) per-
chlorate complexes of the achiral pyridono crown ether
10. As the asymmetric unit contains two formula units
of this complex salt, a principal observation for the
(R)-1-phenylethylammonium perchlorate 1:1:1 complex
of 10 (10-(R)-PEA) is that geometric properties of both
complexes are identical within experimental error (Fig.
3). This applies regarding both their respective shape,
Table 1. Hydrogen bonding dimensions in the 10-(R)-PEA
complex
DꢀH···A
DꢀH1(L%) H···A(L%) D···A(L%) DꢀH···A(°)
N1ꢀH1···N21 0.97
1.94
2.45
1.92
2.40
2.25
2.882(0)
3.021(9)
2.922(4)
3.01(0)
165
114
167
131
145
N1ꢀH3···O3
N1ꢀH3···O6
N1ꢀH2···O9
1.03
1.03
0.85
N1ꢀH2···O12 0.85
2.987(0)
(dimensions, conformation) and also other characteris-
tics (e.g. H-bridge pattern, disorder appearance etc.).
Since these structure models agree well and may be
considered reliable, some interesting questions such as
tautomerization of the pyridone rings and H-bonding
pattern (Table 1) can be answered. (i) All experimentally
localized relevant H-atoms show that all hydrogens of the
ammonium group engage in H-bridges in a uniform
manner. As mentioned earlier, even the appearance of
bifurcated H-bonds is identical in both independent
complexes (Fig. 3). (ii) A hydrogen atom involved in
H-bonds to one of the oxygen atoms of a perchlorate
anion was found at the oxygen atom of the pyridine
moiety, indicating that it is in the hydroxypyridine
tautomeric form. This is also reflected in the respective
bond lengths (Fig. 4).
Figure 3. One of the 10-(R)-PEA complexes in its asymmetric
unit, with atomic numbering, H-bridges are in broken lines,
extensive disorder of the perchlorate anion is visible.
Figure 4. Averaged bond length schematics of the pyridine
moiety in the 10-(R)-PEA complex.

J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
2807
The interplanar angle of 56.7° in the 10-(R)-PEA
complex of the aromatic rings (shown in the side
view in Fig. 5) suggests that there is no p–p-stacking
interaction between the two aromatic rings. The evi-
dence of a clear and uniform H-bonding pattern are
consistent with that fixation of the ammonium ion in
the crown ether cavity being mainly due to H-bond-
ing. Although one of the hydrogens of one of the
methylene groups points towards the center of the
arene ring, the distance being the sum of the corre-
,
sponding van der Waals radii (2.93 A), this interac-
tion should be rather weak and probably illustrates
only an electrostatically favorable disposition (Fig.
5).
Figure 5. Side view of the 10-(R)-PEA complex with rele-
vant H-bridges in broken lines, also showing one of the
methylene hydrogens juxtaposed against the aromatic ring
of the cation.
Figure 6. Anisotropic displacement representation of one of
the 10-BA complexes in the asymmetric unit. H-bridges in
broken lines.
3. Experimental
3.1. General
Infrared spectra were recorded on a Zeiss Specord IR
75 spectrometer. Optical rotations were taken on a
Perkin–Elmer 241 polarimeter that was calibrated by
measuring the optical rotations of both enantiomers of
menthol. 1H (500 MHz) and 13C (125 MHz) NMR
spectra were taken on a Bruker DRX-500 Avance
spectrometer. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of
Organic Chemistry, L. Eo¨tvo¨s University, Budapest,
Hungary. MASS Spectra: VG-2AB-2 SEQ reverse
geometry mass spectrometer. Melting points were taken
on a Boetius micro melting point apparatus and were
uncorrected. Starting materials were purchased from
Aldrich Chemical Company unless otherwise noted.
Silica gel 60 F254 (Merck) and aluminum oxide 60 F254
neutral type E (Merck) plates were used for TLC.
Aluminum oxide (neutral, activated, Brockman I) and
silica gel 60 (70–230 mesh, Merck) were used for
column chromatography. Romil Ltd. (Cambridge UK)
SuperPurity Solvent grade THF stored under argon
was used in all reactions. Solvents were dried and
purified according to the well established methods.26
Evaporations were carried out under reduced pressure.
The 1:1:1 complex of 10 with benzylammonium per-
chlorate 10-BA crystallizes in a centrosymmetric space
group with only one molecule in the asymmetric unit.
Its overall appearance is rather similar to that of the
10-(R)–PEA complex. In the solid state the pyridine
ring is also in the hydroxy tautomer, the principal
H-bonding scheme is identical and anion binding to
the -OH group basic functions behave alike. Hydro-
gen bridges are short for the ammonium moiety (typi-
,
cal H···A distances range from 1.82–2.25 A, DꢀH···A
angles 160–178°) and are normal for -OH···anion con-
,
tacts (mean distance is 2.00 A, DꢀH···A angle 166°)
for both complexes of 10. The benzene ring of the
ammonium salt is even more remote to the hydroxy-
pyridine ring and to the closest methylene group
,
(H···ring center distance 3.2–3.3 A). Presence of the
pyridol tautomer in the complexes [10-(R)-PEA and
10-BA]has also been substantiated by NMR and IR
evidence, notably the absence of a low field 13C signal
at around 180 ppm and the band at around 1635
cm−1, both characteristic for the carbonyl group (Fig.
6).

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3.2. (4R,5R,13R,14R)-4,5,13,14-Tetrabutyl-3,6,9,12,15-
pentaoxa-21-azabicyclo-[15.3.1]heneicosa-1(21),17,19-
triene, (R,R,R,R)-15
19.5, 19.6, 32.0, 70.6, 70.8, 71.0, 71.4, 71.5, 73.8, 78.6,
80.2, 121.3, 137.2, 158.4; MS (FAB): calcd for
C35H64NO9 642.4586. Found: 642.4581 (M+H); IR
(film): w=2960, 2928, 2838, 2856, 1592, 1460, 1376,
1264, 1112, 872, 812, 760 cm−1.
To a suspension of sodium hydride (0.30 g; 7.5
mmol, 60% dispersion in mineral oil) in THF (5 mL)
(R,R,R,R)-21 (736 mg, 1.76 mM) in THF (12 mL)
was added dropwise at 0°C under argon. The mixture
was stirred for 15 min at rt and for 1 h at 50°C.
Ditosylate 23 (787 mg, 1,76 mM) in THF (15 mL)
was added at −78°C. The mixture was let to warm up
to rt and stirring was continued for 24 h. After evap-
oration the residue was taken up in CH2Cl2 and
extracted with water. The aqueous phase was
extracted three times with CH2Cl2. The combined
organic phase was dried over MgSO4 and evaporated.
The residue was purified by chromatography first on
Al2O3, (toluene/EtOH, 100:1) then on silica gel (tolu-
ene/EtOH, 9:1) to give (R,R,R,R)-15 (482 mg, 53%).
3.5. (4S,5S,13S,14S)-19-Benzyloxy-4,5,13,14-tetra-
butoxymethyl-3,6,9,12,15-pentaoxa-21-azabicyclo-
[15.3.1]heneicosa-1(21),17,19-triene, (S,S,S,S)-18
Diol (S,S,S,S)-22 (1,17 g, 2.18 mM) and ditosylate 24
(1,20 g, 2,18 mM) were converted to (S,S,S,S)-18
(1.04 g, 64%) as described above for compound
1
(R,R,R,R)-15. [h]D23=+20.5 (c 1.9, CH2Cl2). H NMR
(CDCl3): l=0.91 (mc, 12H), 1.37 (mc, 8H), 1.56 (mc,
8H), 3.40–3.67 (m, 24H), 3.79 (mc, 4H), 4.65–4.81 (m,
4H), 5.12 (s, 2H), 6.96–7.05 (m, 2H), 7.35–7.44 (m,
5H); 13C NMR (CDCl3): l=14.2, 19.6, 32.0, 70.0,
70.5, 70.8, 71.5, 71.5, 71.6, 73.5 78.5, 79.4, 107.9,
127.9, 128.5, 128.9, 136.1, 160.2, 166.3; MS (FAB):
calcd for C42H70NO10 748.5000. Found: 748.5011 (M+
H); IR (film): w=2960, 2928, 2888, 1600, 1456, 1372,
1112, 736, 696 cm−1.
1
[h]2D3=+8.9 (c 0.62, CH2Cl2). H NMR (CDCl3): l=
0.89 (mc, 12H), 1.31 (mc, 16 H),1.45 (mc, 8H), 3.35
(mc, 2H), 3.43 (mc, 2H), 3.47 (mc, 4H), 3.59 (mc,
2H), 3.71 (mc, 2H), 4.70 (d, J=12 Hz, 2H), 4.88 (d,
J=12 Hz, 2H), 7.37 (m, 2H), 7.72 (s, 1H); 13C NMR
(CDCl3): l=14.1, 22.8, 22.9, 2 8.0, 28.1, 30.1, 30.2,
70.4, 70.9, 73.5, 80.1, 82.1, 121.0, 137.1, 158.3; MS
(FAB): calcd for C31H56NO5 522.4146. Found:
522.4159 (M+H);. IR (film): w=2928, 2888, 2864,
1592, 1460, 1376, 1352, 1268, 1244, 1108, 992, 816,
760 cm−1.
3.6. (4R,5R,13R,14R)-4,5,13,14-Tetrabutyl-3,6,9,12,15-
pentaoxa-21-azabicyclo-[15.3.1]heneicosa-17,20-diene-
19(21H)-one, (R,R,R,R)-19
Hydrogenation of (R,R,R,R)-16 (410 mg, 0.6 mmol)
in EtOH (20 mL) over 10% palladium-on-charcoal
gave after the usual work-up and chromatography on
silica gel (benzene/EtOH/25% aq. NH4OH, 9:2:0.2)
(R,R,R,R)-19 (278 mg, 80%) as an amorphous solid.
3.3. (4R,5R,13R,14R)-19-Benzyloxy-4,5,13,14-
tetrabutyl-3,6,9,12,15-pentaoxa-21-azabicyclo-
[15.3.1]heneicosa-1(21),17,19-triene, (R,R,R,R)-16
1
[h]2D5=+1.61 (c 5.6, CH2Cl2); H NMR (CDCl3): l=
0.92 (t, J=7.0 Hz, 12H), 1.32–1.50 (m, 24H), 3.28
(mc, 4H), 3.63 (mc, 4H), 3.78 (mc, 2H), 3.90 (mc,
2H), 4.47 (d, J=12.1 Hz, 2H), 4.58 (d, J=12.1 Hz,
2H), 6.44 (s, 2H), 10.41 (br s, 1H); 13C NMR
(CDCl3): l=14.3, 23.2, 27.4, 31.0, 31.3, 69.3, 71.0,
81.8, 82.5, 104.2, 148.0, 180.6. MS (FAB): calcd for
C31H56NO6 538.4108. Found: 538.4129 (M+H); IR
(film): w=3302, 2928, 2838, 2856, 1636, 1536, 1450,
1376, 1130, 868 cm−1.
Diol (R,R,R,R)-21 (500 mg, 0.84 mM) and ditosylate
24 (462 mg, 0.84 mM) was converted to (R,R,R,R)-16
(272 mg, 52%) as described above for compound
(R,R,R,R)-15. [h]2D5=+35.1 (c 0.52, CH2Cl2). 1H
NMR (CDCl3): l=0.99 (mc, 12H), 1.32 (mc, 12H),
1.49 (mc, 12H), 3.36 (mc, 2H), 3.47 (mc, 6H), 3.58
(mc, 2H), 4.66 (d, J=13 Hz, 2H) 4.81 (d, J=13 Hz,
2H) 5.14 (s, 2H), 6.99 (s, 2H), 7.39 (mc, 5H); 13C
NMR (CDCl3): l=14.3, 22.9, 23.1, 28.2, 28.4, 30.2,
30.3, 70.0, 70.6, 71.1, 73.4, 80.1, 82.2, 107.7, 127.8,
128.5, 128.9, 136.1, 160.4, 166.4; MS (FAB): calcd for
C38H62NO6 628.4577. Found: 628.4563 (M+H); IR
(film): w=2936, 2872,1600, 1576, 1456, 1324, 1108,
864, 736, 696 cm−1.
3.7. (4S,5S,13S,14S)-4,5,13,14-Tetrabutoxymethyl-
3,6,9,12,15-pentoxa-21-azabicyclo-[15.3.1]heneicosa-
17,20-diene-19(21H)-one, (S,S,S,S)-20
(S,S,S,S)-18 (934 mg, 1.25 mM) was hydrogenated on
10% palladium-on-charcoal catalyst (0.2 g) in EtOH
using the standard methodology to give (S,S,S,S)-20
(800 mg, 98%) as an oil. [h]2D5=+18.3 (c 1.58,
CH2Cl2). 1H NMR (CDCl3): l=0.90 (t, J=7.0 Hz,
12H), 1.33 (q, J=7.0 Hz, 8H), 1.51 (quint, J=7.0
Hz, 8H), 3.41 (quint, J=7.0 Hz, 8H), 3.52–3.65 (m,
16H), 3.88 (mc, 4H), 4.53 (d, J=13 Hz, 2H) 4.63 (d,
J=13 Hz, 2H) 6.16 (s, 2H), 10.88 (bs, 1H); 13C
NMR (CDCl3): l=14.1, 19.5, 31.9, 69.5, 70.2, 70.5,
70.5, 70.7, 71.6, 71.6, 78.8, 78.9, 114.4, 147.7, 180.3;
MS (FAB): calcd for C35H64NO10 658.4530. Found:
658.4564 (M+H); IR (film): w=3304, 2936, 2888,
2872, 1960, 1632, 1464, 1376, 1116 cm−1.
3.4. (4S,5S,13S,14S)-4,5,13,14-Tetrabutoxymethyl-
3,6,9,12,15-pentaoxa-21-azabicyclo-[15.3.1]heneicosa-
1(21),17,19-triene, (S,S,S,S)-17
Diol (S,S,S,S)-22 (515 mg, 0.96 mM) and ditosylate
23 (428 mg, 0.96 mM) were converted to (S,S,S,S)-17
(101 mg, 16%) as described above for compound
1
(R,R,R,R)-15. [h]D25=+7.3 (c 0.45, CH2Cl2). H NMR
(CDCl3): l=0.92 (mc, 12H), 1.38 (mc, 8H), 1.55 (mc,
8H), 3.39–3.95 (m, 28H), 4.83 (d, J=13 Hz, 2H) 4.89
(d, J=13.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.67 (t,
1H, J=8 Hz); 13C NMR (CDCl3): l=14.1, 14.2,

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2809
3.8. (5R,6R,14R,15R)-6,14-Dibutyl-7,10,13-trioxanon-
adecane-5,15-diol, (R,R,R,R)-21
3.11. (R,R)-6-Benzyloxy-decan-5-ol, (R,R)-27
To dioxolane (R,R)-26 (6.6 g, 26.8 mM) in 200 mL of
CH2Cl2 DIBALH (90 mL, 1.5 M in toluene) was added
dropwise at 0°C. The mixture was stirred for 24 h at rt.
The reaction mixture was then cooled to 0°C and
methanol (12 mL) followed by sat. aq. NH4Cl solution
(30 mL) was added carefully. 5% aqueous HCl was
added and the organic phase was washed with water,
dried over MgSO4 and the solvent was evaporated. The
residue was purified by chromatography on silica gel
(hexane/acetone, 9:1) to give (R,R)-27 (5.6 g, 84%) as
an oil. [h]2D5=+22.3 (c 0.87, CH2Cl2). 1H NMR
(CDCl3): l=0.93 (mc, 6H), 1.33–1.67 (m, 12H), 2.21
(bs, 1H), 3.29 (q, J=5.5 Hz, 1H), 3.56 (m, 1H), 4.51 (d,
J=11.3 Hz, 1H), 4.68 (d, J=11.3 Hz, 1H), 7.31–7.37
(m, 5H); 13C NMR (CDCl3): l=14.5, 23.2, 23.5, 27.8,
28.4, 30.5, 33.7, 72.9, 73.1, 82.9, 128.2, 128.3, 128.9,
139.0; IR (film): w=3550, 3510, 3440, 3405, 3030, 3000,
2935, 2910, 1495, 1466, 1450, 1380, 1215, 1100, 1075,
1020, 745, 705 cm−1.
Dibenzylether (R,R,R,R)-29 (600 mg, 1.0 mM) was
debenzylated as described above for compound
(R,R,R,R)-19 to give (R,R,R,R)-21 (402 mg, 97%) as an
oil after chromatography on silica gel (hexane/acetone,
1
10:1). [h]2D5=+11.0 (c 0.36, CH2Cl2). H NMR (CDCl3):
l=0.91 (t, J=7.0 Hz, 12H), 1.31–1.53 (m, 24H), 3.10
(mc, 2H), 3.42 (bs, 2H), 3.47 (mc, 2H), 3.60 (mc, 2H),
3.68 (quint, J=7 Hz, 4H), 3.80 (mc, 2H); 13C NMR
(CDCl3): l=14.3, 23.0, 23.2, 27.9, 28.0, 31.2, 33.1, 70.4,
70.9, 73.7, 84.9. IR (film): w=3456, 2928, 2872, 1464,
1424, 1348, 1328, 1272, 1100, 732 cm−1.
3.9. (7S,8S,16S,17S)-8,16-Bis(butoxymethyl)-
5,9,12,15,19-pentaoxatricosan-7,17-diol, (S,S,S,S)-22
To a stirred suspension of sodium hydride (2.7 g, 90
mmol, as 80% dispersion in mineral oil) in THF (20
mL) (S,S)-32 (10.7 g, 33.0 mM) in THF (20 mL) was
added dropwise at 0°C under an argon atmosphere.
The mixture was stirred for 15 min at 0°C and for 1 h
at 50°C. Diethylene glycol di-p-tosylate 28 (4.3 g, 10
mM) in THF (15 mL) was added at 0°C. The reaction
mixture was maintained at 60°C for 2 h, and then for
24 h at rt. The solvent was evaporated and water was
added. The aqueous phase was extracted three times
with CH2Cl2. The combined organic phases were dried
over MgSO4 and evaporated. The crude (S,S,S,S)-33
was subjected to catalytic hydrogenation in EtOH (50
mL) over 10% palladium on charcoal as described
above for compound (R,R,R,R)-19 to yield (S,S,S,S)-
22 (2.5 g, 45%) and (S,S)-1,4-O,O%-dibutylthreitol (1.8
g) after purification by chromatography on silica gel
3.12. (5R,6R,14R,15R)-5,15-Dibenzyloxy-6,14-dibutyl-
7,10,13-trioxanonadecane, (R,R)-29
To a stirred suspension of sodium hydride (260 mg, 6.5
mmol, as a 60% dispersion in mineral oil) in THF (10
mL) (R,R)-27 (1.2 g, 4.55 mM) in THF (10 mL) was
added at 0°C under an argon atmosphere. The mixture
was stirred for 15 min at 0°C and for 1 h at 50°C.
Diethylene glycol di-p-tosylate 28 (0.624 g, 1.51 mM) in
THF (5 mL) was added at 0°C. The reaction mixture
was maintained at 60°C for 2 h, and then for 24 h at rt.
The solvent was evaporated and water was added. The
aqueous phase was extracted three times with CH2Cl2.
The combined organic phase was dried over MgSO4
and evaporated. The residue was purified by chro-
matography on silica gel (hexane:EtOAc, 30:1) to yield
(R,R)-29 (0.658 g, 73%). [h]2D3=+27.4 (c 0.54, CH2Cl2).
1H NMR (CDCl3): l=0.89 (t, J=7 Hz, 6H), 0.90 (t,
J=7 Hz, 6H), 1.30 (mc, 12H), 1.44 (mc, 8H), 1.56 (mc,
4H), 3.33 (mc, 2H), 3.41 (mc, 2H), 3.59 (mc, 4H), 3.63
(mc, 2H), 3.70 (mc, 2H), 4.55 (d, J=11.5 Hz, 2H) 4.63
(d, J=11.5 Hz, 2H) 7.26–7.36 (m, 10H). 13C NMR
(CDCl3): l=14.5, 14.6, 23.3, 28.6, 30.1, 30.3, 70.5, 71.3,
73.1, 80.8, 82.1, 127.9, 128.4, 128.7, 139.5; IR (film):
w=3088, 3064, 3048, 3032, 2952, 1496, 1456, 1376,
1248, 1208, 1096, 736, 696 cm−1.
1
(CH2Cl2/acetone 9:1). [h]2D3=+22.2 (c 1.0, CHCl3). H
NMR (CDCl3): l=0.92 (t, J=7.3 Hz, 12H), 1.36 (mc,
8H), 1.55 (mc, 8H), 3.17 (bs, 2H), 3.43–3.67 (m, 24H),
3.79 (mc, 2H), 3.92 (mc, 2H); 13C NMR (CDCl3):
l=14.1, 19.5, 32.0, 70.6, 70.8, 71.1, 71.3, 71.5, 71.6,
80.2; IR (film): w=3448, 2928, 2896, 2872, 1728, 1464,
1376, 1268, 1120, 768 cm−1.
3.10. (R,R)-2-Phenyl-4,5-dibutyl-1,3-dioxolane, (R,R)-
26
Benzaldehyde dimethylacetal (4.9 g, 32 mM) and p-
toluenesulfonic acid (260 mg, 1.4 mM) was added to
(R,R)-2523 (4.7 g, 27 mM) in DMF (20 mL). The
reaction mixture was maintained at 60°C until the
reaction was completed. The mixture was then poured
into an ice-cold solution of NaHCO3 (3%, 150 mL).
The resulting suspension was extracted with ether (3×
100 mL), then the combined organic layers was washed
with water (70 mL). The organic phase was dried over
MgSO4 and evaporated to give (R,R)-26 (6.6 g, 100%)
as an oil. [h]2D3=+16.7 (CHCl3, c 1.14). 1H NMR
(CDCl3): l=0.94 (2t, J=7.0, 6H), 1.41 (mc, 6H), 1.55
(mc, 3H), 1.67 (mc, 3H), 3.79 (mc, 2H), 5.89 (s, 1H),
7.36–7.40 (m, 3H), 7.51 (m, 2H); 13C NMR (CDCl3):
l=14.2, 22.9, 23.0, 28.4, 28.5, 32.9, 33.0, 81.8, 83.1,
102.8, 126.9, 128.5, 129.3, 138.7; IR (film): w=2960,
2936, 2864, 1460, 1408, 1380, 1220, 1092, 1076, 1004,
760, 696 cm−1.
3.13. (S,S)-2-Phenyl-4,5-bis(butoxymethyl)-1,3-diox-
olane, (S,S)-31
To a suspension of sodium hydride (2.12 g, 80% disper-
sion in mineral oil) in DMF (10 mL) diol (S,S)-3025
(5.3 g, 25.2 mM) in DMF (10 mL) was added at 0°C
under an argon atmosphere. The mixture was stirred
for 15 min at rt and for 1 h at 50°C. The reaction
mixture was cooled to 0°C and butyl bromide (9.8 g, 70
mM; 7.6 mL) in DMF (10 mL) was added. The mixture
was stirred for 4 h at rt, then the solvent was evapo-
rated, water added and the aqueous phase was
extracted three times with CH2Cl2. The combined
organic phase was dried over MgSO4 then the solvent

2810
J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
was evaporated. The residue was purified by chro-
matography on silica gel (hexane/acetone, 30:1) to give
(S,S)-31 (7.0 g, 86%) as an oil. [h]2D5=+0.7 (c 2.40,
mg, 64%,) were filtered off and air dried, mp 197–198°C
(EtOH). Crystals for X-ray analysis were prepared by
letting a nearly saturated solution of the salt to evapo-
rate slowly at rt. 1H NMR (CDCl3+CD3OD, 1:1):
l=3.57, 3.64, 3.66 (3×s, 16H), 3.96 (s, 2H), 4.35 (4H),
4.60 (br s, 3H), 6.55 (br s, 2H), 7.37 (s, 5H); 13C NMR
(CDCl3+CD3OD, 1:1): l=69.3, 69.5, 69.8, 70.0, 128.6,
128.9, 129.4, 132.4;. IR (KBr): w=3320, 3130, 3040,
2915, 1610, 1540, 1450, 1355, 110, 1080 cm−1.
1
CH2Cl2), [h]H25g 365=+21.0 (c 2.40, CH2Cl2). H NMR
(CDCl3): l=0.92 (t, J=7.0 Hz, 3H), 0.93 (t, J=7.0 Hz,
3H), 1.38 (mc, 4H), 1.58 (mc, 4H), 3.51 (mc, 4H), 3.64
(mc, 4H), 4.12 (mc, 1H), 4.21 (mc, 1H), 5.95 (s, 1H),
7.35 (m, 3H), 7.49 (m, 2H). 13C NMR (CDCl3): l=
14.1, 19.5, 31.9, 71.3, 71.5, 71.8, 78.2, 78.6, 104.3, 127.0,
128.4, 129.5, 137.9;. IR (film): w=2944, 2928, 2896,
1460, 1376, 1280, 1220, 1112, 984, 744, 672 cm−1.
3.17. Crystal data for the 10–(R)-PEA complex
C23H35ClN2O10, Fwt.: 534.98, colorless prism, space
3.14. (S,S)-1,4-O,O%-Dibutyl-2-O-benzylthreitol (S,S)-
,
,
group P21, a=8.850(1)A, b=25.848(3) A, c=11.820(1)
32
3
,
,
A, h=90°, i=96.11(2)°, k=90°, V=2688.5(5) A , Z=
4, DX=1.322 Mg/m3. A crystal of 10–(R)-PEA was
mounted on a glass fiber on an Enraf–Nonius CAD4
diffractometer (graphite monochromator; Cu-Ka radia-
To dioxolane (S,S)-31 (4.8 g, 14.9 mM) in CH2Cl2 (150
mL) DIBALH (65 mL, 1.2 M in toluene) was added
dropwise at 0°C. The mixture was stirred for 24 h at rt.
The reaction mixture was then cooled to 0°C and
methanol (10 mL) followed by the careful addition of
sat. aq. NH4Cl (20 mL) and then 5% aqueous HCl. The
organic phase was washed with water, dried over
MgSO4 and the solvent was evaporated. The residue
was purified by chromatography on silica gel (hexane/
acetone, 5:1) to give (S,S)-32 (4.0 g, 83%) as an oil.
,
tion, u=1.54180 A) at 295(2) K in the range 3.425q5
66.40° using ꢀ/2q scans. A total of 10286 reflections
were collected of which 9205 were unique [R(int)
=
0.0124, R(|)=0.0575]; intensities of 5170 reflections
were greater than 2|(I). Empirical absorption
correction27 was applied to the data (the minimum and
maximum transmission factors were 0.5423 and
0.7219). Initial structure model was refined by direct
methods28 and completed in subsequent difference syn-
1
[h]2D5=+12.5 (c 1.59, MeOH). H NMR (CDCl3): l=
0.91 (mc, 6 H), 1.35 (mc, 4H), 1.56 (mc, 4H), 2.65 (bs,
1H), 3.41–3.49 (m, 6H), 3.61 (m, 1H), 3.66 (mc, 2H),
3.87 (mc, 1H), 4.60 (d, J=11.7 Hz, 1H), 4.76 (d,
J=11.7 Hz, 1H), 7.35 (mc, 5H). 13C NMR (CDCl3):
l=14.4, 19.8, 32.2, 32.2, 71.3, 71.4, 71.7, 71.9, 72.0,
73.4, 78.0, 128.2, 128.4, 128.8, 138.9; IR (film): w=3464,
3032, 3016, 2960, 2944, 2888, 1456, 1376, 1120, 736, 684
cm−1.
theses.
Anisotropic
full-matrix
least-squares
refinement29 on F2 for all non-hydrogen atoms yielded
R1=0.0480 and wR2=0.1109 for 5170 [I>2|(I)] and
R1=0.0995 and wR2=0.1258 for all 9205 intensity
data, (goodness-of-fit=0.926, Flack x=0.01(2).30
Hydrogen atomic positions were calculated from
assumed geometries except those of the ammonium
group and that of the -OH which were located in
difference electron density maps. Hydrogen atoms were
included in structure factor calculations but they were
not refined. The isotropic displacement parameters of
the hydrogen atoms were approximated from the U(eq)
value of the atom they were bonded to.
3.15. [(R)-PEA] complex of 3,6,9,12,15-pentoxa-21-
azabicyclo-[15.3.1]heneicosa-17,20-diene-19(21H)-one 10
Compound 10 (66 mg, 0.2 mmol) and (R)-1-
phenylethylammonium perchlorate (44 mg, 0.2 mmol)
in EtOH (1 mL) was dissolved by heating, allowed to
stand for 1 day and then in a refrigerator overnight.
The crystals (67 mg, 64%,) were filtered off and air
dried, yield 62 mg (58%), mp 159–161°C. Crystals for
X-ray analysis were prepared by letting a nearly satu-
3.18. Crystal data, for the 10–BA complex
C22H33ClN2O10, Fwt.: 520.95, space group P21/a, a=
,
,
,
8.436(1) A, b=26.265(2) A, c=11.733(1) A, h=90°,
i=95.49(1)°, k=90°, V=2587.8(4) A , Z=4, F(000)=
3
,
1
1104, Dx=1.337 Mg/m3. A crystal of 10·BA was
mounted on a glass fiber on a diffractometer (graphite
monochromator; Cu-Ka radiation, u=1.54180 A) at
rated solution of the salt to evaporate slowly at rt. H
NMR (CDCl3+CD3OD, 1:1): l=1.34 (d, 3H), 3.28,
3.36, 3.38 (3×s, 16H), 4.00–4.11 (m, 5H), 4.29 (br s,
3H), 6.17 (br s, 2H), 7.08 (s, 5H); 13C NMR (CDCl3+
CD3OD, 1:1): l=19.3, 47.5, 47.7, 47.9, 50.8, 69.3, 69.5,
69.8, 70.0, 128.8, 128.7, 128.9, 137.5;. IR (KBr): w=
3310, 3220, 3110, 2905, 1610, 1540, 1450, 1350, 110,
1080, 1040, 1020, 690, 610 cm−1.
,
293(2) K in the range 3.375q575.74° using ꢀ/2q
scans. A total of 5861 reflections were collected of
which 5340 were unique [R(int)=0.0086, R(|)=0.0268];
intensities of 2997 reflections were greater than 2|(I).
An empirical absorption corrections27 was applied to
the data (the minimum and maximum transmission
factors were 0.5334 and 0.7151). Initial structure model
was refined by direct methods28 and completed in sub-
sequent difference syntheses. Anisotropic full-matrix
least-squares refinement29 on F2 for all non-hydrogen
atoms yielded R1=0.0624 and wR2=0.1802 for 2997
[I>2|(I)] and R1=0.1004 and wR2=0.2015 for all 5340
intensity data, (goodness-of-fit=0.995, extinction
coefficient=0.0005(3).30 Hydrogen atomic positions
3.16. Benzylammonium perchlorate (BA) complex of
3,6,9,12,15-pentaoxa-21-azabicyclo-[15.3.1]heneicosa-
17,20-diene-19(21H)-one 10
Compound 10 (66.2 mg, 0.2 mmol) and 1-benzylammo-
nium perchlorate (41.5 mg, 0.2 mmol) in EtOH (10 mL)
was dissolved by heating, allowed to stand for 1 day
and then in a refrigerator overnight. The crystals (67

J. Gerencse´r et al. / Tetrahedron: Asymmetry 14 (2003) 2803–2811
2811
were calculated from assumed geometries except those
of the ammonium group and that of the -OH which
were located in difference electron density maps.
Hydrogen atoms were included in structure factor cal-
culations but they were not refined. The isotropic dis-
placement parameters of the hydrogen atoms were
approximated from the U(eq) value of the atom they
were bonded to.
11. Horva´th, V.; Taka´cs, T.; Horvai, Gy.; Huszthy, P.; Brad-
shaw, J. S.; Izatt, R. M. Anal. Lett. 1997, 30, 1591–1609.
12. Bradshaw, J. S.; Nakatsuji, Y.; Huszthy, P.; Wilson, B.
E.; Dalley, N. K. J. Heterocyclic Chem. 1986, 23, 353–
360.
13. Horva´th, G.; Huszthy, P. Tetrahedron: Asymmetry 1999,
10, 4573–4583.
14. Horva´th, G.; Huszthy, P.; Szarvas, S.; Szo´ka´n, G.; Redd,
J. T.; Bradshaw, J. S.; Izatt, R. M. Ind. Eng. Chem. Res.
2000, 39, 3576–3581.
15. Izatt, R. M.; LindH, G. C.; Bruening, R. L.; Huszthy, P.;
McDaniel, C. W.; Bradshaw, J. S.; Christensen, J. J.
Anal. Chem. 1988, 60, 1694–1699.
16. Izatt, R. M.; LindH, G. C.; Clark, G. A.; Nakatsuji, Y.;
Bradshaw, J. S.; Lamb, J. D.; Christensen, J. J. J. Mem-
brane Sci. 1987, 31, 1–13.
CCDC 213627 [10–(R)-PEA] and CCDC 213628 [10–
BA) contain the supplementary crystallographic data
for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/prods/encifer/
(or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK, (fax (+44)-
1223-336-033 or deposit@ccdc.cam.ac.uk).
17. Gokel, W. G.; Nakano, A. In Crown Compounds: Toward
Future Applications; Cooper, S. R., Ed.; VCH Publishers:
New York, 1992; Chapter 1.
Acknowledgements
18. Tsukube, H.; Yamada, T.; Shinoda, S. Ind. Eng. Chem.
Res. 2000, 39, 3412–3418.
19. Erickson, S. D.; Still, W. C. Tetrahedron Lett. 1990, 31,
4243–4256.
20. Sasaki, S.; Naito, H.; Maruta, K.; Kawahara, E.; Maeda,
M. Tetrahedron Lett. 1994, 35, 3337–3340.
Financial support from the Hungarian Scientific
Research Fund (OTKA grants T-038393 and TO-
042642) is gratefully acknowledged.
21. Shibutani, Y.; Mino, S.; Long, S. S.; Moriuchi-
Kawakami, T.; Yakabe, K.; Shono, T. Chem. Lett. 1997,
49.
22. Horva´th, G.; Rusa, C.; Ko¨nto¨s, Y.; Gerencse´r, J.;
Huszthy, P. Synth. Commun. 1999, 29, 3719.
23. Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.;
Hartung, J.; Kawanami, Y.; Lu¨bben, D.; Manoury, E.;
Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56,
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