Chromatographic enantioseparation of racemic α-(1- naphthyl)ethylammonium perchlorate by a Merrifield resin-bound enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand

Article abstract of DOI:10.1016/S0957-4166(99)00515-7

Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the chromatographic enantioseparation of rac

Full text of DOI:10.1016/S0957-4166(99)00515-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4573–4583
Chromatographic enantioseparation of racemic α-(1-naphthyl)-
ethylammonium perchlorate by a Merrifield resin-bound
enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand
György Horváth a and Péter Huszthy b,∗
aDepartment of Organic Chemistry, Technical University of Budapest, H-1521 Budapest, Hungary
bResearch Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
Received 27 October 1999; accepted 15 November 1999
Abstract
Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was
attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the
chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate. Also, a new chiral
pyridono-18-crown-6 ligand (S,S)-6, used for the synthesis of (S,S)-1 and (S,S)-2, was prepared in two different
ways. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Separation of enantiomers is a ubiquitous procedure in organic and analytical chemistry, in drug
research and industry. The best method for enantiomeric separation, especially on analytical and semi-
preparative scales, is chiral liquid chromatography (CLC), using chiral stationary phases (CSPs), which
can be prepared by attaching suitable chiral molecules (chiral selectors) to achiral matrixes such as
silica gel or polymeric resins. Among the chiral selectors, homochiral† crown ethers have been used
successfully for enantioseparation of racemic organic ammonium salts.1–13 Homochiral crown ethers
have the ability of enantiomeric recognition, i.e. the homochiral crown ether host can differentiate
between the enantiomers of the guest (a chiral ammonium salt, for example). Enantiomeric recognition of
chiral organic ammonium salts by homochiral crown ethers was first studied by Cram and co-workers.14
We have reported the preparation of a number of homochiral pyridino-18-crown-6-type ligands,15–20
and have thoroughly studied the factors governing their enantioselective complexation abilities with the
enantiomers of selected chiral organic primary ammonium salts.21,22 We have shown that three main
∗
†
Corresponding author. E-mail: huszthy.szk@chem.bme.hu
Homochiral means single pure enantiomer throughout.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00515-7
tetasy 3150

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non-covalent intermolecular forces are responsible for the different stability of the complexes formed
by homochiral pyridino-crown ethers and the selected chiral organic ammonium salts containing an aryl
group: the tripod-like hydrogen bonding between the pyridine nitrogen and two alternate oxygens in
the macro ring of the crown ether host and the three protons of the ammonium salt guest; the π–π
stacking between the pyridine unit of the host and the aromatic ring of the ammonium salt guest; and
the steric hindrance between certain hydrogens of the host and the guest.21,22 When both partners are
chiral these interactions, especially steric hindrance, are different in the two diastereomeric complexes.
These differences result in enantioselectivity and if of sufficient magnitude, may provide the possibility
that these homochiral crown ether hosts can be used for the separation of enantiomers of chiral organic
ammonium salt guests by CLC.
In the late 1970s, Cram and co-workers reported their pioneering work on the attachment of substituted
bis(dinaphthyl)-22-crown-6 ligands to both silica gel1 and a polymer resin.2 Using these CSPs they
separated several racemic organic ammonium salts, mainly protonated amino acid esters.1,2
A few years ago, we attached dimethyl- and diphenyl-substituted chiral pyridino-18-crown-6 ligands
to silica gel, and it was shown that these CSPs separated racemic α-(1-naphthyl)ethylammonium
perchlorate (NEA).15 Recently, we attached a homochiral di-tert-butylpyridino-18-crown-6 ligand to
silica gel and enantiomers of selected racemic ammonium perchlorates were efficiently separated on
this CSP.23
In continuation of our studies on developing novel CSPs capable of resolving racemic organic
ammonium salts by CLC, we report here the preparation of a new homochiral pyridino-18-crown-6 ligand
(S,S)-1 and its attachment to Merrifield polymer resin by a covalent bond (see Fig. 1). The resulting
adsorbent (S,S)-5 was used as a CSP in the enantioseparation of racemic NEA. The advantage of this
Merrifield-type resin based CSP is its high chemostability, which permits its application even under hard
conditions (for example, using nucleophilic solvents and strong acidic or basic conditions).
Fig. 1. Structures of the new chiral pyridino- and pyridono-18-crown-6 ligands and the modified Merrifield resin
In this paper we describe three ways for the preparation of ligand (S,S)-1, report the synthesis of a new
proton-ionizable pyridono-crown compound (S,S)-6 and also two other new pyridino-crown compounds,

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4575
with a benzyloxy (S,S)-3 and a 3-trityloxypropyloxy group (S,S)-2 at position 4 of the pyridine ring
(see Fig. 1 and Scheme 1). Pyridono-crown (S,S)-6 was transformed by regioselective alkylation with
3-chloropropan-1-ol and 1-chloro-3-trityloxypropane 11 into (S,S)-1 and (S,S)-2, respectively, opening
an alternative way for the preparation of 4-alkoxy-substituted pyridino-18-crown-6 ligands (see Scheme
1).
Scheme 1. Preparation of new chiral macrocycles
2. Results and discussion
All new crown compounds were prepared by the Williamson-type ether synthesis by reacting 4-
substituted-2,6-pyridinedimethanol-bis(4-methyl-benzenesulphonate) 7, 8,24 924 and the enantiome-
rically pure α,ω-dimethyl-substituted tetraethylene glycol (S,S)-1025 to give ligands (S,S)-2, (S,S)-3,
and (S,S)-4. Crude products were purified by Al2O3 column chromatography. Protecting groups were
removed either by treatment with acetic acid in a water–ethanol mixture [in the case of (S,S)-2 and
(S,S)-4], which removes both trityl and tetrahydropyranyl moieties allowing the formation of (S,S)-1 and
(S,S)-6, respectively, or catalytic hydrogenation [in the case of (S,S)-3] to give (S,S)-6 (Scheme 1).
Enantiomerically pure (S,S)-10 was prepared as reported25 except that (S,S)-1225 was deblocked by an
acidic ion-exchange resin which increased the yield and purity of (S,S)-10 (Scheme 2).
There is a method reported in the literature26 for the synthesis of pyridonedimethanol 13 (the starting
material for ditosylate 7), but it has only been characterized by its 1H NMR spectrum. Now we describe
a different method for deprotection of 4-[(tetrahydro-2H-pyran-2-yl)oxy]-2,6-pyridinedimethanol 1427
and fully characterize the product (Scheme 3). A band at 1640 cm−1 in the IR spectrum for compound 13

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Scheme 2. Preparation of chiral tetraethylene glycol (S,S)-10
is indicative of the pyridone carbonyl function27–29 and compound 13 also has a singlet at δ=6.32 ppm
in its 1H NMR spectrum indicative of the two olefinic protons in a pyridone ring.27–29
Scheme 3. Preparation of ditosylate 7
Reaction of trityl chloride with 3-chloropropan-1-ol in pyridine gave ether 11, which is a useful
reagent for the formation of a suitable linker for macrocycle (S,S)-1. With the sixth atom provided by
the chloromethyl group of the resin, the tether is a six-membered chain. Treatment of 13 with 11 in DMF,
in the presence of potassium carbonate gave diol 15 in a good yield (Scheme 3). The disappearance of
the band at 1640 cm−1 in the IR spectrum and the singlet at δ=6.32 ppm in the 1H NMR (both for 13),
together with the appearance of the band at 1605 cm−1 in the IR spectrum of 15, and a singlet at δ=6.72
ppm in the 1H NMR spectrum are confirmative of the 4-alkoxypyridine system of 15.15,16,23,27 Diol 15
was reacted with tosyl chloride in tetrahydrofuran using finely powdered potassium hydroxide as a base
to produce ditosylate 7 by the method well established in our laboratories15–19,29 (Scheme 3).
We found another route for the production of 4-alkoxy-substituted-pyridino-18-crown-6 compounds
by the alkylation of the pyridono ligands. Reaction of (S,S)-6 with 3-chloropropan-1-ol and 11, respecti-
vely, resulted in the formation of two macrocycles identical with (S,S)-1 and (S,S)-2 (Scheme 1). Similar
to the alkylation of 13, no N-alkyl product was detectable in the 1H NMR spectrum of the crude products.
Attachment of the homochiral dimethylpyridino-18-crown-6 ligand (S,S)-1 to the Merrifield resin is
shown in Scheme 4. Ligand (S,S)-1 was treated with sodium hydride and the resulting alkoxide was
reacted with the chloromethyl groups of the resin. Because of the heterogenous phase conditions, the
reaction was quite slow and reasonable conversion required a long time. According to elemental analysis
the resin contained 0.56 mmol ligand/g. From the liquid phase, a new bis-crown compound, (S,S,S,S)-16,
was isolated and its structure was determined by NMR, IR and MS spectroscopy and elemental analysis.
This compound could be formed by nucleophilic attack of the alkoxide of (S,S)-1 at position 4 of the

G. Horváth, P. Huszthy / Tetrahedron: Asymmetry 10 (1999) 4573–4583
4577
pyridine ring of another (S,S)-1 molecule, followed by the release of 1,3-propanediol. The rate of the
latter reaction is comparable to that with the chloromethyl groups of the resin, since the amount of dimer
(S,S,S,S)-16 was relatively large, and no monomer [(S,S)-1] was present in the recovered product.
Scheme 4. Attachment of the homochiral dimethylpyridino-18-crown-6 ligand (S,S)-1 to Merrifield resin
The chromatographic resolution of NEA on CSP (S,S)-5 is shown in Fig. 2. The separation experiments
were carried out in a manner similar to that reported.15,23 A concentrated solution of racemic NEA was
placed on the column and eluted with different solvent mixtures. A mixture of methanol:acetonitrile (1:5)
provided proper concentration of fractions and reduced tailing. The amount of (R)- and (S)-salts in each
fraction was determined by polarimetry using calibration curves.23 As shown in Fig. 2, (S)-NEA passes
through the column faster because of the lower stability of the homochiral complex formed by (S,S)-1
and (S)-NEA21 (see Fig. 2).
3. Conclusions
The results obtained here show that the new chiral pyridino-18-crown-6 ligands (S,S)-2, (S,S)-3
and (S,S)-4 containing 3-trityloxypropyloxy, benzyloxy and tetrahydropyranyloxy groups at position
4 of the pyridine ring can be prepared with reasonable yields from the appropriate 4-substituted 2,6-
pyridinedimethanol ditosylates and the chiral dimethyl-substituted tetraethylene glycol using NaH as a
base in THF. Removal of the protecting groups from (S,S)-3 and (S,S)-4 resulted in the novel pyridono-
crown (S,S)-6 which was transformed by regioselective O-alkylation with 3-chloropropan-1-ol into the
new pyridino-ligand (S,S)-1 containing the 3-hydroxypropyloxy chain at position 4 of the pyridine ring.
Deblocking the trityl group of (S,S)-2 also resulted in the formation of (S,S)-1 which was attached
covalently to the Merrifield resin by an ether bond, and this novel CSP almost completely separated
the enantiomers of racemic NEA by column chromatography.

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Fig. 2. A smoothed curve showing the separation of (R)- and (S)-NEA on (S,S)-5 using 5:1 methanol:acetonitrile as an eluent
(for details, see the Experimental section)
4. Experimental
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 rotation of both enantiomers
1
of menthol. H (500 MHz) and 13C (125 MHz) spectra were taken on a Bruker DRX-500 Avance
spectrometer in CDCl3 unless otherwise indicated. Molecular weights were determined by a VG-ZAB-2
SEQ reverse geometry mass spectrometer. Elemental analyses were performed in the Microanalytical
Laboratory of the Department of Organic Chemistry, L. Eötvös University, Budapest, Hungary. Melting
points were taken on a Boetius micro melting point apparatus and are 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 (70–200 mesh, Merck) were used for column chromatography.
Solvents were dried and purified according to well established methods.30 Evaporations were carried out
under reduced pressure unless otherwise stated.
4.1. (4S,14S)-(+)-19-(3-Hydroxypropyloxy)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo-
[15.3.1]heneicosa-1(21),17,19-triene (S,S)-1
A mixture of (S,S)-2 (9.4 g, 14.6 mmol, see below), glacial acetic acid (175 mL) and water (60 mL)
was stirred at 80°C for 90 min. After the reaction was completed the solvents were evaporated and traces
of acetic acid were removed by repeated distillation of toluene from the residue. The remaining oil was
triturated with water (60 mL) and crystals of triphenylmethanol were filtered off, and washed with water
(3×20 mL). Filtrate and washings were evaporated and the residual oil was dried by repeated distillation
of benzene to give (S,S)-1 (5.6 g, 96%) as a colourless oil; [α]D25=+17.9 (c 0.695, CH2Cl2); IR (film)
νmax 3650, 3000, 2980, 2970, 2950, 2930, 2860, 1640, 1620, 1600, 1570, 1470, 1380, 1350, 1250, 1100,

G. Horváth, P. Huszthy / Tetrahedron: Asymmetry 10 (1999) 4573–4583
4579
1050, 800 cm−1; 1H NMR δ 1.15 (d, 6H, J=6 Hz), 2.03 (quin, 2H, J=6 Hz), 2.58 (s, 1H, disappears by
addition of D2O), 3.45–3.90 (m, 16H), 4.17 (t, 2H, J=6 Hz), the benzylic -CH2- gives a diastereotopic AB
spin system: δA=4.65, δB=4.78, JAB=13 Hz, 4H, 6.74 (s, 2H); 13C NMR δ 17.08, 31.76, 59.39, 65.15,
70.60, 70.78, 71.57, 73.70, 75.90, 106.93, 160.04, 166.15; MS: (FAB, glycerol matrix) 400 (M+H+);
anal. calcd for C20H33NO7: C, 60.13; H, 8.33; N, 3.51. Found: C, 60.38; H, 8.17; N, 3.55.
4.1.1. Preparation of (S,S)-1 from (S,S)-6
A mixture of (S,S)-6 (280 mg, 0.82 mmol), 3-chloro-1-propanol (130 mg, 1.38 mmol) and K2CO3
(340 mg, 242 mmol) was stirred in pure and dry DMF (5 mL), under argon, at 80°C for 2 days. The
solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate (50 mL) and water (25
mL). The aqueous phase was extracted with ethyl acetate (1×25 mL). The combined organic phase was
dried (MgSO4), filtered and the solvent was removed. The residue was purified by chromatography on
alumina to give (S,S)-1 (205 mg, 62.6%); [α]D25=+16.6 (c 0.410, CH2Cl2). All spectral data of (S,S)-1
were identical to those of (S,S)-1 prepared from (S,S)-2.
4.2. General procedure for preparation of chiral pyridino-18-crown-6 ligands (S,S)-2, (S,S)-3 and
(S,S)-4
A suspension of NaH (2.0 g, 50 mmol, 60% mineral oil dispersion) in pure and dry THF (30 mL)
was stirred under argon at 0°C. A solution of (S,S)-10 (3.5 g, 15.8 mmol) in THF (70 mL) was added to
the suspension dropwise. The mixture was stirred at 0°C for 10 min, at rt for 30 min and refluxed for 4
h. The mixture was cooled to −60°C and a solution of 4-alkoxy-2,6-pyridinedimethanol-bis(4-methyl-
benzenesulphonate) (15.8 mmol) in THF (55 mL) was added, and the mixture was stirred at −60°C
for 30 min than at rt for 1 week. The solvent was removed and the residue dissolved in a mixture of
ether (300 mL) and ice cold water (100 mL). The aqueous phase was extracted with ether (4×100 mL).
The combined organic phase was dried (MgSO4), filtered and the solvent was removed. The residue
was purified by column chromatography on alumina to give the pyridino-18-crown-6 compounds as
1
colourless oils [(S,S)-2: 2.9 g (43.2%); (S,S)-3: 2.33 g (34.2%)]. [For crude (S,S)-4 only the H NMR
spectrum was taken before it was transformed into (S,S)-6 (see below).]
4.2.1. (4S,14S)-(+)-19-[(3-Trityloxypropyloxy]-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo-
[15.3.1]heneicosa-1(21),17,19-triene (S,S)-2
[α]D25=+1.8 (c 2.114, benzene); IR (film) νmax 3100, 3080, 3040, 3010, 2990, 2950, 2920, 2890,
1605, 1590, 1500, 1460, 1380, 1360, 1340, 1100, 760, 750, 710, 640, cm−1; 1H NMR δ 1.16 (d, 6H, J=6
Hz), 2.06 (quin, 2H, J=6 Hz), 3.28 (t, 2H, J=6 Hz), 3.42–3.65 (m, 12H), 3.78–3.88 (m, 2H), 4.19 (t, 2H,
J=6 Hz), the benzylic -CH2- gives a diastereotopic AB spin system: δA=4.73, δB=4.78, JAB=13 Hz, 4H,
6.78 (s, 2H), 7.17–7.47 (m, 15H); 13C NMR δ 17.14, 29.58, 59.68, 64.82, 70.60, 71.80, 73.54, 86.53,
106.85, 126.93, 127.74, 128.17, 128.59, 128.97, 144.10, 160.02, 161.04; MS: (FAB, glycerol matrix) 642
(M+H+).
4.2.2. (4S,14S)-(+)-19-Benzyloxy-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-
1(21),17,19-triene (S,S)-3
[α]D25=+5.2 (c 1.322, benzene); IR (film) νmax 3090, 3070, 2960, 2910, 2880, 1600, 1580, 1490,
1450, 1370, 1340, 1250, 1130, 1110, 1050, 980, 850, 740, 690 cm−1; 1H NMR δ 1.15 (d, 6H, J=6 Hz),
3.42–3.61 (m, 12H), 3.81 (t, 2H, J=6 Hz), the benzylic -CH2- gives a diastereotopic AB spin system:
δA=4.73, δB=4.77, JAB=13 Hz, 4H, 5.12 (s, 2H), 6.87 (s, 2H), 7.35–7.43 (m, 5H); 13C NMR δ 17.29,

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69.97, 70.79, 70.96, 71.95, 73.84, 76.13, 107.32, 127.76, 128.47, 128.88, 136.11, 160.39, 166.06; HRMS
calcd for C24H33NO6: 431.2308. Found: 431.2290.
4.2.3. (4S,14S)-19-Tetrahydropyranyloxy-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-
heneicosa-1(21),17,19-triene (S,S)-4
1H NMR δ 1.15 (d, 6H, J=6 Hz), 1.53–1.86 (m, 6H), 3.43–3.66 (m, 14H), 3.92 (t, 2H, J=6 Hz), the
benzylic -CH2- gives a diastereotopic AB spin system: δA=4.74, δB=4.78, JAB=13 Hz, 4H, 5.42 (quin,
1H), 6.81 (s, 2H).
4.2.4. Preparation of (S,S)-2 starting from (S,S)-6
A mixture of (S,S)-6 (62 mg, 0.18 mmol), 11 (64 mg, 0.183 mmol) and K2CO3 (80 mg, 0.55 mmol)
was stirred in pure and dry DMF (5 mL) under argon at 100°C for 24 h. The solvent was evaporated and
the residue was dissolved in a mixture of CH2Cl2 (50 mL) and water (20 mL). The aqueous phase was
extracted with CH2Cl2 (4×30 mL). The combined organic phase was dried (MgSO4), filtered and the
solvent was removed. The residue was purified by column chromatography on alumina to give (S,S)-2
(100 mg, 85%) as a colourless oil. Spectral data and physical properties of (S,S)-2 prepared in this way
were identical to those of (S,S)-2 obtained as described above.
4.3. Modified Merrifield resin (S,S)-5 and side product (S,S,S,S)-16
To a stirred suspension of NaH (830 mg, 20.7 mmol, 80% dispersion in mineral oil) in dry THF (10
mL) was added a solution of (S,S)-1 (5.6 g, 14 mmol) in THF (90 mL) under argon at 0°C. The mixture
was stirred at 0°C for 10 min, at rt for 40 min, and then at reflux temperature for 4 h. The reaction
mixture was cooled to 0°C, and Merrifield resin (11.6 g, Aldrich, 2% cross-linked, 200–400 mesh, 1 meq
Cl/g; anal: Cl, 3.51%) was added. The mixture was refluxed for 7 days without stirring in order to avoid
milling of the resin. The modified resin was filtered and washed with solvents in the following order:
THF (4×20 mL), iPrOH (1×20 mL), MeOH (3×20 mL), water (3×20 mL), MeOH (1×40 mL), CH2Cl2
(2×40 mL), ether (2×20 mL). The filtrate and washings were combined and evaporated, and the residue
was purified by column chromatography on alumina to give 2.1 g (41%) of dimer (S,S,S,S)-16 as a pale
yellow oil. Analysis of the modified resin [(S,S)-5]: C, 84.10; H, 7.69; N, 0.79; Cl, 0.00%. This means
that it contained 0.56 mmol of crown-compound for each gram of (S,S)-5 (yield: 14.7 g).
4.3.1. 1,3-Bis[19-(4S,14S)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),
17,19-trienyloxy]-propane (S,S,S,S)-16
[α]D25=+12.0 (c 0.300, CH2Cl2); IR (film) νmax 3100, 3040, 2950, 2880, 2850, 1600, 1580, 1500,
1
1450, 1440, 1370, 1330, 1170, 1080, 1020, 900, 850, 760, 690, 540 cm−1; H NMR δ 1.17 (d, 12H,
J=7 Hz), 2.29 (quin, 2H, J=6 Hz), 3.45–3.61 (m, 24H), 3.78–3.85 (m, 4H), 4.23 (t, 4H, J=6 Hz), the
benzylic -CH2- gives a diastereotopic AB spin system: δA=4.72, δB=4.76, JAB=13 Hz, 8H, 6.82 (s, 4H);
13C NMR δ 17.27, 28.90, 64.27, 70.77, 70.92, 71.82, 73.84, 76.98, 107.16, 160.20, 166.19; MS: (FAB
glycerol matrix) 723 (M+H+); anal. calcd for C37H58N2O12: C, 61.52; H, 8.09; N, 3.88. Found: C, 61.71;
H, 8.17; N, 3.65%.

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4.4. (4S,14S)-(+)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-17,20-diene-
19-(21H)-one (S,S)-6
A mixture of crude (S,S)-4 (5.5 g), ethanol (100 mL), water (2 mL) and glacial acetic acid (3 mL) was
stirred for one night at rt (TLC monitoring in 1:20 MeOH:CH2Cl2 on silica). The solvent was evaporated
and the traces of acetic acid were removed by repeated distillation of toluene from the mixture. The
residue was purified by column chromatography on alumina to give a slightly yellow oil (overall yield
of cyclization and hydrolysis: 1.48 g, 27.4%.); [α]D25=+24.2 (c 0.808, CH2Cl2); IR (film) νmax 3100,
2990, 2950, 2900, 2870, 2850, 1640, 1580, 1550, 1530, 1460, 1380, 1250, 1110, 1090, 1040, 1000, 920,
880 cm−1; 1H NMR δ 1.18 (d, 6H, J=6 Hz), 3.4–3.7 (m, 12H), 3.78 (t, 2H, J=6 Hz), the benzylic -CH2-
gives a diastereotopic AB spin system: δA=4.59, δB=4.61, JAB=13 Hz, 4H, 6.42 (s, 2H), 11.01 (s, 1H,
NH); 13C NMR δ 16.22, 67.28, 70.28, 70.91, 74.75, 75.48, 114.60, 147.51, 181.20; HRMS calcd for
C17H27NO6: 341.1838. Found 341.1823; anal. calcd for C17H27NO6·0.5 H2O: C, 58,31; H, 8.06; N,
4.00. Found: C, 58.39; H, 8.24; N, 3.84.
4.4.1. Preparation of (S,S)-6 starting from (S,S)-3
A solution of (S,S)-3 (2.33 g) in methanol (50 mL) was hydrogenated in the presence of Pd/C catalyst
(380 mg, Merck palladium/charcoal; activated, 10% Pd). After 5 min the reaction was complete. The
catalyst was filtered off and washed with methanol (2×10 mL). The filtrate and washings were evaporated
to give pure (S,S)-6 as a pale yellow oil (1.77 g, 96%). Physical properties and spectral data of (S,S)-6
prepared this way were identical to those of (S,S)-6 obtained as described above.
4.5. 4-(3-Trityloxypropyloxy)-2,6-pyridinedimethanol-bis(4-methyl-benzenesulphonate) 7
A suspension of finely powdered KOH (12.6 g, 268 mmol) in dry THF (45 mL) was vigorously stirred
under argon at 0°C. First a solution of 15 (20.5 g, 45 mmol) in THF (120 mL), and then a solution of tosyl
chloride (22.9 g, 120 mmol) in THF (120 mL) were added to the suspension. The mixture was stirred
at 0°C for 2 h and at rt for 4 h. The solvent was removed and the residue was dissolved in a mixture of
CH2Cl2 (400 mL) and ice-water (200 mL). The organic phase was dried (MgSO4) and filtered, and the
solvent was removed. The residue was recrystallized from a mixture of CH2Cl2 and ether to give pale
yellow crystals of 7 (29.5 g, 86%); mp: 126–128°C; IR (KBr) νmax 3160, 3120, 3090, 3030, 2990, 2490,
1650, 1600, 1598, 1570, 1490, 1440, 1350, 1330, 1170, 1150, 1000, 900, 790, 780, 700, 670, 620, 500
1
cm−1; H NMR δ 2.04 (quin, 2H, J=6 Hz), 2.39 (s, 6H), 3.29 (t, 2H, J=6 Hz), 4.09 (t, 2H, J=6 Hz),
4.97 (s, 4H), 6.75 (s, 2H), 7.21–7.28 (m, 13H), 7.42 (d, 6H, J=8 Hz), 7.79 (d, 4H, J=8 Hz); 13C NMR δ
21.63, 29.48, 59.43, 65.38, 71.24, 86.64, 107.76, 127.05, 127.82, 128.06, 128.63, 129.92, 132.75, 144.07,
145.12, 155.06, 166.67.
4.6. (2S,12S)-2,12-Dimethyl-4,7,10-trioxatridecane-2,12-diol (S,S)-10
A solution of (2S,12S)-2,12-bis[tetrahydropyranyloxy]-2,12-dimethyl-4,7,10-trioxatridecane-2,12-
diol [(S,S)-1225] (22.3 g, mmol) in MeOH (300 mL) was stirred with acidic ion-exchange resin (8
g, Fluka Amberlite® IR-120), at rt for 18 h. The resin was filtered off, washed and the filtrate and
washings were evaporated. The slightly coloured crude product was purified by fractional distillation
under reduced pressure to give (S,S)-10 as a colourless liquid (11.2 g, 80%, bp: 109–111°C/0.1 mmHg).
Spectral data and physical properties of (S,S)-10 were identical to those reported for (S,S)-10 in the
literature.25

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G. Horváth, P. Huszthy / Tetrahedron: Asymmetry 10 (1999) 4573–4583
4.7. 3-Chloro-1-trityloxypropane 11
To a stirred solution of 3-chloro-1-propanol (10.7 g, 111 mmol) in dry pyridine (30 mL) was added a
solution of trityl chloride (31.6 g, 113 mmol) in pyridine (90 mL) at rt dropwise. The mixture was stirred
for 1 week (TLC monitoring in 1:2 EtOH:toluene on silica). The solvent was removed and the residue
was dissolved in a mixture of water (400 mL) and ether (800 mL). The organic phase was shaken with
saturated brine (1×150 mL), dried (MgSO4), filtered and the solvent was evaporated to give a slightly
coloured oil, which crystallized from EtOH in a refrigerator overnight. Recrystallization from a mixture
of CH2Cl2–MeOH gave pure 11 (22.7 g, 61%), mp: 73–75°C; IR (KBr) νmax 3080, 3030, 3020, 2970,
2930, 2880, 1520, 1480, 1360, 1110, 1080, 910, 900 cm−1; 1H NMR δ 1.96 (quin, 2H, J=6 Hz), 3.20 (t,
2H, J=6 Hz), 3.68 (t, 2H, J=6 Hz), 7.06–7.53 (m, 15H).
4.8. Bis[2,6-hydroxymethyl]pyridine-4(1H)-one 13
A solution of 4-tetrahydropyranyloxy-2,6-pyridinedimethanol (14) (10 g, 41.8 mmol) in a mixture
of EtOH (250 mL), water (5 mL) and glacial acetic acid (5 mL) was stirred at 120°C for 2 h. After
the reaction was completed the mixture was stored at 0°C overnight. The crystals were filtered off, and
recrystallized from ethanol to give white needles of 13 (4.5 g, 70%), mp: 187–189°C; IR (KBr) νmax
3340, 3120, 2940, 2920, 2900, 2840, 1640, 1600, 1550, 1520, 1500, 1470, 1320, 1190, 1090, 1020,
1010, 880, 810, 530 cm−1; 1H NMR (DMSO-d6) δ 4.40 (s, 4H), 5.38 (s, 3H, disappears by addition of
D2O), 6.32 (s, 2H); MS: (FAB, glycerol matrix) 155 (M+); anal. calcd for C7H9NO3: C, 54.19; H, 5.85.
Found: C, 54.33; H, 6.00.
4.9. 4-(3-Trityloxypropyloxy)-2,6-pyridinedimethanol 15
A mixture of 13 (7.75 g, 50.0 mmol), 11 (16.85 g, 50.0 mmol) and anhydrous K2CO3 (23.5 g, 150.0
mmol) was stirred in dry DMF (150 mL) under argon at 110°C for 72 h. After the reaction was completed
the solvent was removed and the residue was dissolved in a mixture of CHCl3 (500 mL) and ice-water
(150 mL). The aqueous phase was shaken with CHCl3 (3×200 mL). The combined organic phase was
shaken with 10% NaOH solution (200 mL) and water (200 mL), dried (Na2SO4), filtered and the solvent
was evaporated. The residue was triturated with ether, stored in a refrigerator for one night to give 15
as white crystals (20.0 g, 80%), mp: 168–170°C; IR (KBr) νmax 3430, 3130, 3080, 3060, 3030, 2990,
2950, 2930, 2920, 1605, 1580, 1490, 1470, 1440, 1360, 1130, 1060, 970, 710, 660, 590 cm−1; 1H NMR
(DMSO-d6) δ 2.00 (quin, 2H, J=6 Hz), 3.22 (t, 2H, J=6 Hz), 4.12 (t, 2H, J=6 Hz), 4.21 (s, 4H), 6.72 (s,
2H), 6.98–7.52 (m, 15H).
4.10. Enantiomeric separation of racemic NEA on CSP (S,S)-5 by chromatography
Racemic NEA was prepared as reported earlier.16 The racemic salt (50 mg) was dissolved in 0.5 mL
of the eluent and was placed onto the column containing (S,S)-5 (14 g) and eluted with a mixture of
methanol:acetonitrile (1:5). The flow rate was 0.4 mL/min. Each fraction (10 mL) was evaporated, the
salt was dissolved in methanol and the optical rotation was measured. Amounts of enantiomers were
calculated relying upon a calibration curve in the same manner as reported earlier.23

G. Horváth, P. Huszthy / Tetrahedron: Asymmetry 10 (1999) 4573–4583
4583
Acknowledgements
Financial support by the Hungarian Scientific Research Found (OTKA T-14942 and T-25071) is
gratefully acknowledged.
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