Enantioseparation of racemic organic ammonium perchlorates by a silica gel bound optically active di-tert-butylpyridino-18-crown-6 ligand

Article abstract of DOI:10.1016/S0957-4166(99)00163-9

Both enantiomers of the novel chiral di-tert-butylpyridino-18-crown-6 ligand (R,R)-7 and (S,S)-7 containing an allyloxy group on the pyridine subcyclic unit were prepared by the reaction of 4-allyloxy-2,6-pyridinedimethyl ditosylate 9 and the enantiomers of di-tert-butyl-substituted tetraethylene glycol (R,R)-8 and (S,S)-8 in the presence of a strong base. One of them, (R,R)-7, was covalently attached to silica gel, and this chiral stationary phase (CSP) separated four selected racemic organic ammonium perchlorates into their enantiomers by column chromatography.

Full text of DOI:10.1016/S0957-4166(99)00163-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2087–2099
Enantioseparation of racemic organic ammonium perchlorates by
a silica gel bound optically active di-tert-butylpyridino-
1
8-crown-6 ligand
a
b,∗
c
c
Zoltán Köntös, Péter Huszthy, Jerald S. Bradshaw and Reed M. Izatt
a
Institute for Organic Chemistry, Technical University Budapest, H-1521 Budapest, Hungary
b
Research Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
c
Department of Chemistry, Brigham Young University, Provo, Utah 84602, USA
Received 31 March 1999; accepted 27 April 1999
Abstract
Both enantiomers of the novel chiral di-tert-butylpyridino-18-crown-6 ligand (R,R)-7 and (S,S)-7 containing
an allyloxy group on the pyridine subcyclic unit were prepared by the reaction of 4-allyloxy-2,6-pyridinedimethyl
ditosylate 9 and the enantiomers of di-tert-butyl-substituted tetraethylene glycol (R,R)-8 and (S,S)-8 in the presence
of a strong base. One of them, (R,R)-7, was covalently attached to silica gel, and this chiral stationary phase (CSP)
separated four selected racemic organic ammonium perchlorates into their enantiomers by column chromatography.
©
1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiomeric resolution using a chiral stationary phase (CSP) has been an expanding field of research
during the last two decades in order to meet the strong demand for the determination of enantiomeric
composition and in the separation of racemic mixtures of drugs, pesticides and other fine chemicals of
1–6
importance.
Enantiomeric recognition in chromatographic terms means preferential interaction of one enantiomer
of a racemic mixture with the CSP which can lead to chromatographic resolution.7 In the last quarter
of a century there has been great interest in designing new CSPs capable of resolving different classes
,8
5–8
of compounds. The study of enantiomeric separations of amines and protonated amines (amino acids
and their derivatives, for example) is of significance since these compounds are basic building blocks of
biomolecules.
∗
Corresponding author. E-mail: huszthy.szk@chem.bme.hu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00163-9

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Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
Figure 1. Chiral pyridino-18-crown-6 ligands and CSPs based on enantiomerically pure chiral pyridino-18-crown-6 ligands
covalently attached to silica gel
Among several types of compounds studied, such as amino acids (native and derivatized), peptides,
cyclodextrins (native or derivatized) and linear derivatized carbohydrates (cellulose or amylose), chiral
crown ethers containing the dinaphthyl moiety as a chiral barrier have been used as successful selectors
for CSPs in determinations of the enantiomeric compositions and in separations of amine and protonated
amine compounds.9–21
Recently we reported the enantioseparation of racemic [α-(1-naphthyl)ethyl]ammonium perchlorate
+
−
(
NapCH(Me)NH ClO ) using CSPs (S,S)-1 and (R,R)-2 containing pyridino-18-crown-6 ligands as
3 4
2
2
7,9
chiral selectors. As expected from previous studies, the degree of enantiomeric recognition of the
parent ligands (S,S)-3 and (R,R)-4 (see Fig. 1) expressed in the difference of the Gibbs free energies,
+
−
∆
(∆G) for the complexation of (S)- and (R)-NapCH(Me)NH ClO in the same solvent as the eluent
3
4
(
MeOH), paralleled very well the effectiveness of enantiomeric separation on CSPs (S,S)-1 and (R,R)-2.
Our previous studies also showed that (S,S)-5 containing the bulky tert-butyl groups at the stereogenic
centers had the highest enantioselectivity among stable pyridino-18-crown-6 ligands.2
3,24
The other
+
−
advantage of using ligand (S,S)-5 as a selector for enantioseparation of racemic NapCH(Me)NH ClO
3
4
and other racemic organic ammonium salts is not only that the ∆(∆G) value is large, but also that the
individual ∆G values (see Table 1) are relatively small which also favors enantioseparations on a CSP.7
In this paper we report the preparation of CSP (R,R)-6 and its use for enantioseparation of selected
racemic organic ammonium salts.
2. Results and discussion
The two enantiomers of the new di-tert-butyl pyridino-18-crown-6 ligand (R,R)-7 and (S,S)-7 (see
Scheme 1) were prepared from the two enantiomers of the di-tert-butyl-substituted tetraethylene glycol
[
(R,R)-8 and (S,S)-8] and 4-allyloxy-2,6-pyridinedimethyl ditosylate 9 in THF using a strong base NaH
22,25–27
in a similar manner as we described earlier
for obtaining analogous crown ethers. It can also be
seen in Scheme 1 how one of the enantiomers [(R,R)-7] was attached covalently to silica gel to obtain
CSP (R,R)-6. The first step of this procedure was a highly regioselective hydrosilylation reaction using
triethoxysilane and a commercially available Pt catalyst to obtain chiral crown-substituted triethoxysilane

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2089
Table 1
∆
G (kJ/mol) and ∆(∆G) values for the interactions of enantiomerically pure chiral pyridine-
containing ligands with the enantiomers of [α-(1-naphthyl)ethyl]ammonium perchlorate
+
−
(
3 4
NapCH(Me)NH ClO ) at 25°C
(
R,R)-10. The latter was then heated with silica gel using toluene as a solvent in a similar manner as
27
22
described by us earlier for the preparation of CSPs (S,S)-1 and (R,R)-2. The silica gel CSP (R,R)-
6
4
contained approximately 0.43 mmol of chiral crown per gram as determined by elemental analysis.
-Allyloxy-2,6-pyridinedimethyl ditosylate 92
7,28
needed for the synthesis of both enantiomers of the
27
new crown ether (R,R)-7 and (S,S)-7 was prepared as reported. Although we described the synthesis
of one enantiomer of di-tert-butyl-substituted tetraethylene glycol (S,S)-825 earlier, that procedure was
not a convenient one for large scale preparation. Here we report a straightforward preparation of both
enantiomers (R,R)-8 and (S,S)-8 in multigram quantities (see Schemes 2 and 3).
Scheme 1. Preparation of chiral allyloxypyridino-crowns (R,R)-7 and (S,S)-7, and silica gel bound chiral crown (R,R)-6
The preparation of the enantiomerically pure chiral hydroxy acid precursors (R)-14 and (S)-14 is
29
outlined in Scheme 2. Van Draanen et al. described a ‘one pot’ synthesis for racemic hydroxy acid

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Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
Scheme 2. Preparation and resolution of racemic hydroxy acid 14
Scheme 3. Preparation of chiral di-tert-butyl-substituted tetraethylene glycol (R,R)-8 and (S,S)-8
1
4 starting from pinacolone and gaseous Cl . We found that using Br instead of Cl and making other
2 2 2
minor modifications, a more convenient laboratory procedure could be developed for obtaining 14 (see
Scheme 2).
Dibromination of pinacolone in acidic conditions gave 11 which was heated with aqueous NaOH
solution. The α-oxo-aldehyde 12 first formed underwent an internal Cannizzaro reaction in this strong
basic medium resulting in sodium salt 13 which after acidification gave hydroxy acid 14. Racemic acid 14
was resolved into its enantiomers (R)-14 and (S)-14 using (S)-1-phenylethylamine [(S)-PhCH(Me)NH ]
2
30
(
see Scheme 2). Masamune et al. described the preparation of the diastereomeric salt (S)-14-(S)-
PhCH(Me)NH from 1 mol of 14 and 1 mol of resolving agent (S)-PhCH(Me)NH using isopropanol
2
2
(three times) and an ethanol–ether mixture (once) as solvents for recrystallization. As using the latter
solvents for recrystallization did not give satisfactory results in our hands, we used other systems. When
we used 0.5 mol of resolving agent (S)-PhCH(Me)NH for 1 mol of racemic acid 14 and water as a
2
solvent of recrystallization, the diastereomeric salt (R)-14-(S)-PhCH(Me)NH was obtained. Using 1
2
mol of (S)-PhCH(Me)NH for 1 mol of 14 and THF as a solvent of recrystallization, the diastereomeric
2
salt (S)-14-(S)-PhCH(Me)NH was obtained. Both enantiomers of hydroxy acid 14, i.e. (R)-14 and
2

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2091
(
S)-14 were obtained by acidification of diastereomeric salts (R)-14-(S)-PhCH(Me)NH and (S)-14-(S)-
2
PhCH(Me)NH with diluted aqueous HCl followed by extraction with ether. From the aqueous phases
2
+
−
containing (S)-PhCH(Me)NH Cl , the resolving agent [(S)-PhCH(Me)NH ] was recovered by using
3
2
aqueous NaOH followed by extraction with ether in good yields (see Scheme 2).
The preparation of the enantiomers of di-tert-butyl-substituted tetraethylene glycol (R,R)-8 and (S,S)-8
from enantiomerically pure hydroxy acids (R)-14 and (S)-14 is shown in Scheme 3.
Hydroxy acids (R)-14 and (S)-14 were first treated with an excess of dihydropyran (DHP) in the
presence of pyridinium p-toluenesulfonate (PPTS) catalyst to give the bis-tetrahydropyranyl (THP)
derivatives (R)-15 and (S)-15 which were then reduced to give mono-THP-blocked alcohols (R)-16 and
(S)-16. Two moles of alcohols (R)-16 and (S)-16 were deprotonated using NaH in THF and the alkoxides
formed were reacted with one mole of diethylene glycol di-p-tosylate 17 to obtain bis-THP-blocked
+
derivatives of (R,R)-8 and (S,S)-8 which were then deblocked with strong acidic ion-exchange resin (H
form) in methanol to give the two enantiomers of tetraethylene glycol (R,R)-8 and (S,S)-8.
The separations of racemic organic ammonium perchlorates using new silica gel CSP (R,R)-6 are
+
−
shown in Fig. 2 [α-(1-naphthyl)ethylamine hydrogen perchlorate salt, NapCH(Me)NH ClO , 18];
3
4
+
−
Fig. 3 [1-phenylethylamine hydrogen perchlorate salt, PhCH(Me)NH ClO , 19]; Fig. 4 [methyl
phenylalaninate hydrogen perchlorate salt, PhAlaNH ClO , 20]; and Fig. 5 [methyl phenylglycinate
hydrogen perchlorate salt, PhGlyNH ClO , 21]. These separation studies were carried out in a manner
3
4
+
−
3
4
+
−
3
4
22,27
similar to that reported.
Very concentrated methanol/dichloromethane solutions of the racemic
ammonium salts 18–21 were placed on a column containing CSP (R,R)-6 and then the enantiomers of
the ammonium salts 18–21 were eluted with different mixtures of methanol and dichloromethane (see
Experimental). We found that among many solvents and solvent mixtures the different ratios of methanol
and dichloromethane allowed good separations of enantiomers. The amounts of (R)- and (S)-salts in each
fraction were determined by polarimetry using calibration curves (see Experimental).
Because (R,R)-6 interacts more strongly with (S)-salts,2
2,27
(R)-salts pass through the column first and
the (S)-salts last as observed in Figs. 2–5. Studies on using other racemic organic ammonium salts and
improving separations by the change of solvent systems, loading and flow rates are in progress. The
results of these studies will be published later.
Figure 2.

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Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
Figure 3.
Figure 4.
Figure 5.

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2093
3. Experimental
3.1. General
Infrared spectra were obtained 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
1
13
enantiomers of menthol. H (500 MHz) and C (125 MHz) NMR spectra were taken on a Bruker
1
DRX-500 Avance spectrometer and H (80 MHz) NMR spectra were obtained on a Brucker AW-80
spectrometer in CDCl unless otherwise indicated. Molecular weights were determined by a VG-ZAB-2
3
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 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.
Solvents were dried and purified according to the well established3 methods. Evaporations were carried
out under reduced pressure unless otherwise stated.
1
3.2. Silica gel bound chiral crown (R,R)-6 (Scheme 1)
The hydrosilylation reaction of crown ether (R,R)-7 with triethoxysilane, and the attachment of the
resulting triethoxysilyl-derivative (R,R)-10 were carried out in a similar manner as reported by us2
2,27
for
analogous macrocycles. A mixture of (R,R)-7 (9.0 g, 19.3 mmol) and triethoxysilane (5.5 mL, 4.9 g, 29.0
mmol, freshly distilled under Ar) was stirred vigorously at rt in a 50 mL one-necked flask equipped with
a rubber septum. Pt catalyst (SIP 6830.0, ABCR, Karlsruhe, Germany) (10 drops) was added through
1
the rubber septum. After stirring the reaction mixture for 5 days at rt, the H NMR spectrum of a small
aliquot showed that the olefin protons of (R,R)-7 had disappeared. The volatile compounds were removed
1
from the reaction mixture (0.02 mmHg) giving (R,R)-10 (10.04 g, 96%); H NMR (500 MHz) δ 0.77 (t,
J=8 Hz, 2H), 0.96 (s, 18H), 1.24 (t, J=7 Hz, 9H), 1.84 (m, 2H), 3.45–3.67 (m, 12H), 3.61–3.67 (m, 2H),
1
3
4
5
1
3
5
.00 (m, 2H), 4.78–4.85 (m, 4H), 6.83 (s, 2H); C NMR (125 MHz) δ 18.50, 26.63, 26.74, 34.75, 34.77,
8.64, 69.84, 70.70, 71.10, 72.65, 85.34, 88.77, 148.14, 160.40, 166.40. Triethoxysilyl-derivative (R,R)-
0 (10.0 g, 18.5 mmol) was stirred (mechanical stirring) with silica gel (41.0 g Davisil , grade 646,
5–60 mesh, 150 Å) in toluene (680 mL) at 90°C for 5 days. The silica gel was filtered and washed with
™
0% toluene in methanol (3×100 mL) and then with methanol (3×100 mL). The filtrate and washings
were evaporated to give 1.9 g of unreacted organic material. This means that 8.1 g (17.3 mmol, 90%)
of (R,R)-7 was attached to the silica gel. The silica gel containing the bound crown (R,R)-6 was dried
in a vacuum oven at 60°C for 3 h. A sample of blank silica gel was dried the same way and it gave a
combustion analysis of C, 0.00; H, 0.60; N, 0.00. The combustion analysis of (R,R)-6 gave C, 6.44; H,
1.36; N, 0.59. This means that each gram of (R,R)-6 contained 0.42 mmol (by %C) or 0.43 mmol (by
%
H) of the chiral crown.
3
1
.3. 19-Allyloxy-(4R,14R)-(+)-4,14-di-tert-butyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-
(21),17,19-triene (R,R)-7 (Scheme 1)
To a well stirred suspension of NaH (5.51 g, 138 mmol, 60% dispersion in mineral oil) in THF (90
mL) was added dropwise under Ar at 0°C (R,R)-8 (14.84 g, 48.4 mmol) dissolved in THF (460 mL). The

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Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
mixture was stirred at 0°C for 10 min, at rt for 30 min and at reflux temperature for 3 h. The reaction
mixture was cooled to −10°C and 9 (24.8 g, 49.2 mmol) dissolved in THF (520 mL) was added dropwise.
The resulting mixture was stirred at −10°C for 20 min and then at rt for 4 days. After the reaction had
been completed, the solvent was removed. The residue was taken up in a mixture of ether (900 mL), ice
(400 g) and water (400 mL). The resulting mixture was mixed well and separated. The aqueous phase
was shaken with ether (2×600 mL). The combined organic phase was dried (MgSO ), filtered, and the
4
solvent was removed. The residue was purified by column chromatography on neutral alumina using 1%
EtOH in toluene as an eluent to give pure (R,R)-7 (12.0 g, 53%) as an oil; R =0.55 (silica TLC, 17%
f
2
5
EtOH in toluene); [α] =+19.2 (c 1.223, benzene); IR (neat) ν 2960, 2930, 2900, 2870, 1590, 1575,
D
−1 1
1
(
(
7
470, 1450, 1440, 1390, 1360, 1330, 1310, 1100, 1030, 980, 910, 850 cm ; H NMR (500 MHz) δ 0.96
s, 18H), 3.48–3.55 (m, 12H), 3.63–3.68 (m, 2H), 4.60 (d, J=5 Hz, 2H), 4.76–4.86 (m, 4H), 5.32–5.45
m, 2H), 6.01–6.09 (m, 1H), 6.86 (s, 2H); 13C NMR (125 MHz) δ 26.47, 34.60, 68.50, 70.57, 70.95,
+
2.50, 74.22, 85.18, 106.70, 118.40, 132.45, 160.40, 165.70; MS (FAB, glycerol matrix) 466 [M+H] .
Anal. calcd for C H NO : C, 67.07; H, 9.31; N, 3.01. Found: C, 66.98; H, 9.34; N, 3.10.
20
43
6
3
1
.4. 19-Allyloxy-(4S,14S)-(−)-4,14-di-tert-butyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-
(21),17,19-triene (S,S)-7 (Scheme 1)
Compound (S,S)-7 was prepared and purified in the same way as described above for (R,R)-7 starting
2
5
from (S,S)-8 (5.57 g, 24.0 mmol) to give (S,S)-7 (6.48 g, 57%); [α] =−19.0 (c 1.15, benzene). All other
D
physical properties and spectral data were identical to those of (R,R)-7. Anal. calcd for C H NO : C,
20
43
6
67.07; H, 9.31; N, 3.01. Found: C, 66.88; H, 9.44; N, 3.15.
3.5. (R,R)-(−)-1,11-Di-tert-butyl-3,6,9-trioxaundecane-1,11-diol (R,R)-8 (Scheme 3)
To a well stirred suspension of NaH (21.6 g, 544 mmol, 60% dispersion in mineral oil) in THF (100
mL) was added dropwise at 0°C and under Ar alcohol (R)-16 (60.4 g, 298 mmol) dissolved in THF
400 mL). The reaction mixture was stirred at 0°C for 10 min, at rt for 20 min and at reflux temperature
(
for 3 h. The reaction mixture was cooled to 0°C and diethylene glycol di-p-tosylate 17 (60.0 g, 290
mmol) dissolved in THF (110 mL) was added dropwise. Stirring was continued at 0°C for 10 min then
at rt for 4 days. The solvent was removed and the residue was taken up in a mixture of ice (200 g),
water (260 mL) and ether (800 mL). The mixture was shaken well and separated. The aqueous phase
was extracted with ether (2×300 mL). The combined organic phase was shaken with saturated brine
(
500 mL), dried (MgSO ), filtered and the solvent was evaporated. The residue (148.2 g) was stirred
4
®
+
with Amberlite IR-120 strong acidic ion-exchange resin (H form, 26.0 g) in methanol (3.2 L) at rt
for 18 h. After deblocking had been completed the resin was filtered, washed with methanol (3×30 mL)
and the solution was evaporated. The residue was taken up in a mixture of water (140 mL), methanol
(560 mL) and hexane (360 mL). The mixture was shaken well and separated. The aqueous methanol
phase was extracted with hexane (3×100 mL). The combined hexane phase was shaken with 1:4 (v/v)
water:methanol (200 mL). The combined aqueous methanol solution was evaporated. The residue was
taken up in toluene (60 mL) and the solvent was removed. The latter procedure was repeated two more
times to remove water. The crude product was purified by distillation to give (R,R)-8 (30.2 g, 66%); bp:
2
5
1
(
08–110°C (0.1 mmHg); R =0.45 (silica TLC, 9% EtOH in toluene); [α] =−38.2 (c 2.08, benzene)
f
D
25
25
lit. [α] =+38.0 (c 2.08, benzene) for the other enantiomer (S,S)-8). All other physical properties and
D
25
spectral data were identical to those reported for (S,S)-8.

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2095
3.6. (S,S)-(+)-1,11-Di-tert-butyl-3,6,9-trioxaundecane-1,11-diol (S,S)-8 (Scheme 3)
Compound (S,S)-8 was prepared in the same way as described above for (R,R)-8 starting from (S)-16
15.1 g, 74.5 mmol). The crude product was purified by distillation to give (S,S)-8 (7.2 g, 65%); bp:
(
25
1
08–110°C (0.1 mmHg); R =0.45 (silica TLC, 9% EtOH in toluene); [α] =+37.9 (c 2.08, benzene)
f
D
25
25
(lit. [α] =+38.0 (c 2.08, benzene)). All other physical properties and spectral data were identical to
D
25
those reported.
3.7. 4-Allyloxy-2,6-pyridinedimethyl ditosylate 9 (Scheme 1)
Compound 9 was prepared from 4-allyloxy-2,6-pyridinedimethanol and tosyl chloride using powdered
2
7
KOH in THF as reported; (yield: 86%), R =0.6 (silica gel TLC, 9% 2-butanone in toluene); mp:
f
8
0–81°C (MeOH–1,2-dichloroethane) (lit.27 mp: 79–81°C (MeOH–1,2-dichloroethane)). All other phy-
sical properties and spectral data were identical to those reported.
27
3.8. (ꢀ)-2-Hydroxy-3,3-dimethylbutanoic acid 14 (Scheme 2)
Compound 14 was prepared in a similar manner to that reported.29 The main difference was that we
used bromine instead of chlorine. To a stirred mixture of pinacolone (75 mL, 60 g, 0.6 mol) and two drops
of concentrated aqueous HBr was added dropwise under Ar in an ice–salt bath bromine (62 mL, 194 g,
0.775 mol). After adding about 70% of the bromine the reaction mixture solidified, so the temperature
was increased to 75°C, and the rest of the bromine was added at this temperature. After stirring the
reaction mixture at 80°C for another 1 h, 20% aqueous NaOH solution (720 mL) was slowly added. The
resulting mixture was stirred overnight, then cooled to 0°C, and the unreacted pinacolone was removed
by shaking with ether (300 mL). The pH of the aqueous phase was adjusted with concentrated aqueous
HCl to 2, then the solution was shaken with ether (1×600 mL and 3×300 mL). The combined organic
phase was dried (MgSO ), filtered, and the solvent was removed. The crude product was recrystallized
4
from 1,2-dichloroethane to give pure 14 (65.0 g, 82%); R =0.45 (silica gel TLC, 1:2:7 acetic acid:ethyl
f
2
9
acetate:hexane); mp: 86–87°C (lit. mp: 87–88°C (benzene)). All other physical properties and spectral
29
data were identical to those reported.
3.9. (S,R)-(+)-1-Phenylethylammonium 2-hydroxy-3,3-dimethylbutanoate [(R)-14-(S)PhCH(Me)NH2]
(Scheme 2)
To a stirred solution of hydroxy acid 14 (51.4 g, 389 mmol) in water (296 mL) was added at 0°C and
under Ar (S)-1-phenylethylamine (23.6 g, 25 mL, 194.5 mmol). After addition the reaction mixture was
refluxed until a clear solution formed, then it was stored at rt for 6 h and in a refrigerator overnight. The
crude diastereomeric salt was filtered off, dried and recrystallized five times from water (6 mL of water for
each gram of salt) to give optically pure (R)-14-(S)-PhCH(Me)NH salt (12.5 g, 12%); mp: 147–149°C;
2
2
5
[
1
α] =+18.2 (c 2.01, ethanol); IR (KBr) ν 3650–2400 (broad), 1700, 1670, 1630, 1600, 1540, 1500,
D
−1 1
400, 1300, 1200, 1060, 1000, 750, 735, 680 cm ; H NMR (500 MHz, DMSO) δ 0.88 (s, 9H), 1.46 (d,
J=6 Hz, 3H), 3.23 (s, 1H), 4.30 (q, J=6 Hz, 1H), 7.17 (s, disappeared in D O, 4H), 7.38–7.59 (m, 5H).
2
Instead of racemic hydroxy acid 14, the partially resolved 14 which was later recovered from the mother
liquors (THF) of recrystallization of (S)-14-(S)-PhCH(Me)NH (see below) can also be used.
2

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Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
3.10. (S,S)-(−)-1-Phenylethylammonium 2-hydroxy-3,3-dimethylbutanoate [(S)-14-
(
S)-PhCH(Me)NH ] (Scheme 2)
2
To a stirred solution of hydroxy acid 14 (25.7 g, 195 mmol) in THF (400 mL) was added at 0°C and
under Ar (S)-1-phenylethylamine (23.6 g, 25 mL, 195 mmol). After addition the reaction mixture was
refluxed until a clear solution formed, then it was stored at rt for 6 h and in a refrigerator overnight.
The crude diastereomeric salt was filtered off, dried and recrystallized from THF (35 mL of THF for
3
0
each gram of salt) to give optically pure (S)-14-(S)-PhEtNH (18.0 g, 35%); mp: 170–172°C (lit.
2
25
30
20
mp: 171–172°C (ethanol–ether)); [α] =−30.9 (c 2.0, ethanol) (lit. [α] =−33.1 (c 2.00, ethanol)).
Instead of racemic hydroxy acid 14, the partially resolved 14 which was later recovered from the aqueous
D
D
mother liquors of recrystallization of (R)-14-(S) PhEtNH (see above) can also be used. All other physical
2
30
properties and spectral data were identical to those reported.
3.11. (R)- and (S)-2-Hydroxy-3,3-dimethylbutanoic acid (R)-(−)-(14), (S)-(+)-(14) (Scheme 2)
To a well stirred mixture of optically pure diastereomeric salt (R)-14-(S)-PhEtNH or (S)-14-(S)-
2
PhEtNH (50.2 g, 198.2 mmol), ether (500 mL) and water (70 mL) was added dropwise at 0°C 3 M
2
aqueous HCl until the pH of the aqueous phase remained 2 (about 65 mL). The phases were separated
and the aqueous one was extracted with ether (2×150 mL). The combined organic phase was shaken with
saturated brine (500 mL), dried (MgSO ), filtered and the solvent was removed. The crude acids were
4
recrystallized from isopropyl ether–hexane to give pure (R)-(−)-14 (24.7 g, 94%) or (S)-(+)-14 (23.3 g,
3
0
25
8
9%); mp: 53–54°C for (R)-14 and 52–53°C for (S)-14 (lit. mp: 51–52°C for (S)-14); [α] =4.3 (c 4.0,
D
25
30
25
water) for (R)-14 or [α] =+4.3 (c 4.0, water) for (S)-14 (lit. [α] =+4.45 (c 4.0, water) for (S)-14).
D
D
For recovering the resolving agent (S)-PhCH(Me)NH , the aqueous solution containing (S)-
2
+
−
PhCH(Me)NH Cl was made basic with 20% aqueous NaOH and it was extracted with ether (1×400
3
mL and 2×100 mL). The combined organic phase was shaken with saturated brine (2×300 mL), dried
(
MgSO ) and the solvent was removed. The residue was purified by distillation (bp: 71–73°C (12
4
32
22
mmHg)) (lit. bp: 73°C (12 mmHg)) to give pure (S)-PhCH(Me)NH (21–22 g, 88–92%); [α] =−40.2
2
D
32
22
(neat) (lit. [α] =−40.3 (neat)).
D
3.12. Tetrahydropyranyl 2-(R)-(+)-(tetrahydropyranyloxy)-3,3-dimethylbutanoate (R)-15 (Scheme 3)
To a well stirred mixture of (R)-14 hydroxy acid (44.3 g, 0.335 mol) and dihydropyran (DHP) (98
mL, 90 g, 1.07 mol) was added in an ice–salt bath and under Ar pyridinium p-toluenesulfonate (PPTS)
catalyst (3.0 g) and one drop of pyridine. After stirring the reaction mixture in the ice–salt bath for 10
min and at rt for 1 day, the excess DHP was evaporated. The residue was taken up in a mixture of CH Cl2
2
(500 mL), ice (100 g) and water (100 mL). The phases were mixed well and separated. The organic phase
was shaken with water (2×50 mL), dried (MgSO ), filtered and the solvent was removed to give crude
4
(
R)-15 (100.0 g, 99%), which was used without further purification; R =0.8, 0.9 (silica gel TLC, 5%
f
25
MeOH in CH Cl ); [α] =+11.3 (c 2.17, THF); IR (neat) ν 2970, 2920, 2890, 2870, 1730, 1490, 1440,
1
4
2
2
D
−1 1
400, 1370, 1280, 1220, 1170, 1120, 1030, 980, 940, 900, 880, 820 cm ; H NMR (80 MHz) δ 0.90 (s,
.5H), 0.98 (s, 4.5H), 1.16–2.00 (m, 12H), 3.28–4.03 (m, 5H), 4.63–4.82 (m, 1H), 5.95–6.03 (m, 1H).
3.13. Tetrahydropyranyl 2-(S)-(−)-(tetrahydropyranyloxy)-3,3-dimethylbutanoate (S)-15 (Scheme 3)
Compound (S)-15 was prepared in the same way as described above for (R)-15 starting from (S)-14
(
15.7 g, 119 mmol). The crude (S)-15 (35.4 g, 99%) was used without further purification; R =0.8, 0.9
f

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2097
2
5
(
silica gel TLC, 25% ethyl acetate in toluene); [α] =−30.1 (c 2.1, THF); IR (neat) ν 2980, 2930, 2880,
D
−1
2
860, 1730, 1480, 1450, 1410, 1360, 1270, 1210, 1180, 1130, 1030, 1010, 990, 950, 910, 870, 810 cm ;
H NMR (80 MHz) δ 0.96 (s, 4.5H), 1.04 (s, 4.5H), 1.21–1.98 (m, 12H), 3.36–4.05 (m, 5H), 4.52–4.71
1
(m, 1H), 5.98–6.06 (m, 1H).
3.14. 2-(R)-(+)-(Tetrahydropyranyloxy)-3,3-dimethylbutanol (R)-16 (Scheme 3)
To a well stirred suspension of LiAlH (19.0 g, 500 mmol) in ether (350 mL) under Ar at 0°C was
4
slowly added (R)-15 (100.6 g, 335 mmol) dissolved in ether (300 mL). The mixture was stirred at 0°C
for 30 min, at rt for 10 min, and at reflux temperature for 48 h. When the reduction had been completed,
the mixture was cooled in an ice–salt bath and saturated NH Cl (19 mL) and 5% NaOH solution (38 mL)
4
were added very slowly. The resulting mixture was stirred at rt for 4 h, at reflux temperature for 14 h
and at rt again for 6 h. The precipitate was filtered and washed with ether (3×30 mL). The filtrate and
washings were combined and shaken with 5% aqueous Na CO solution (1×50 mL) and water (3×100
2
3
mL) to remove pentane-1,5-diol. The ethereal solution was shaken with saturated brine, dried (MgSO ),
4
filtered and the solvent was removed. The crude product was purified by distillation to give (R)-16 (61.0
2
5
g, 90%); bp: 64–66°C (0.2 mmHg); R =0.5, 0.3 (silica TLC, 9% 2-butanone in toluene); [α] =+14.6
f
D
(
c 3.0, THF); IR (neat) ν 3450 (broad), 2970, 2960, 2940, 2890, 2870, 1490, 1440, 1400, 1370, 1270,
−1 1
1
170, 1130, 1080, 1020, 1000, 980, 920, 900, 870, 800 cm ; H NMR (80 MHz) δ 0.92 (s, 4.5H), 0.99
(
s, 4.5H), 1.35–1.91 (m, 6H), 2.83 (broad s, disappeared with D O, 1H), 3.05–4.01 (m, 5H), 4.43–4.68
2
(m, 1H).
3.15. 2-(S)-(−)-(Tetrahydropyranyloxy)-3,3-dimethylbutanol (S)-16 (Scheme 3)
Compound (S)-16 was prepared in the same way as described above for (R)-16 starting from (S)-15
(
6
35.4 g, 119 mmol). The crude product was purified by distillation to give (S)-16 (20.6 g, 86%); bp:
25
4–66°C (0.2 mmHg); R =0.5, 0.3 (silica TLC, 9% 2-butanone in toluene); [α] =−14.5 (c 3.0, THF);
f
D
IR (neat) ν 3540 (broad), 3010, 2990, 2970, 2940, 2890, 2870, 1480, 1440, 1390, 1330, 1270, 1200,
−1 1
1
4
4
170, 1130, 1110, 1070, 1020, 1000, 950, 920, 900, 870, 850, 800 cm ; H NMR (80 MHz) δ 0.95 (s,
.5H), 1.04 (s, 4.5H), 1.28–1.97 (m, 6H), 2.45 (broad s, disappeared with D O, 1H), 3.11–4.21 (m, 5H),
2
.28–4.98 (m, 1H).
+
−
3
.16. (R)-(+) and (S)-(−) enantiomers of NapCH(Me)NH ClO 18
3 4
23
The preparation of (R)-(+) and (S)-(−) enantiomers of 18 was described earlier ; R =0.8 (silica TLC,
f
2
7
25
9
(
% MeOH in CH Cl ); (R)-(+)-18, mp: 184–185°C (lit. 184–185°C); [α] =+21.3 (c 1.0, ethanol)
2
2
365
27
22
27
25
lit. [α]3 =+21.3 (c 1.0, ethanol)); (S)-(−)-18, mp: 184–185°C (lit. 183–184°C); [α] =−21.25 (c
6
5
3
6
5
27
22
1.0, ethanol) (lit. [α]365=−21.1 (c 1.0, ethanol)).
+
−
3
.17. (R)-(+) and (S)-(−) enantiomers of PhCH(Me)NH ClO 19
3 4
The preparation of (R)-(+) and (S)-(−) enantiomers of 19 was described earlier.23 Pure (R)-(+) and (S)-
−) enantiomers of 19 were obtained by recrystallization from EtOAc:CCl (1:1) (v/v) mixture; R =0.7
(
4
f

2098
Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2
2
(
silica TLC, 16% MeOH in CH Cl ); (R)-(+)-19, mp: 96–97°C; [α] =+16.4 (c 1.0, ethanol); (S)-(−)-
2
2
365
25
1
1
3
9, mp: 96–97°C; [α] =−16.3 (c 1.0, ethanol); IR (KBr) ν 3180, 3080, 2980, 2880, 1640, 1600, 1500,
450, 1380, 1230, 1150, 1120, 1100, 1030, 760, 700, 630 cm ; H NMR (80 MHz) δ 2.97 (d, J=6 Hz,
365
−1 1
H), 2.81–3.17 (m, 1H), 7.30 (broad s, 3H), 7.82 (broad s, 5H).
+
−
3
.18. (R)-(−) and (S)-(+) enantiomers of PhAlaNH ClO 20
3 4
The preparation of (R)-(−) and (S)-(+) enantiomers of 20 was described earlier.23 Pure (R)-(−) and (S)-
+) enantiomers of 20 were obtained by recrystallization from an acetonitrile–CHCl mixture; R =0.55
(
3
f
25
(
silica TLC, 10% MeOH in CH Cl ); (R)-(−)-20, mp: 173–175°C; [α] =−86.3 (c 1.0, ethanol); (S)-
2
2
365
25
(
2
+)-20, mp: 175–176°C; [α] =+86.7 (c 1.0, ethanol); IR (KBr) ν 3200, 3180, 3120, 3080, 2950, 2850,
365
830, 2680, 2600, 2000, 1730, 1600, 1580, 1570, 1560, 1500, 1460, 1430, 1370, 1350, 1300, 1250, 1150,
−1 1
1
120, 1080, 1030, 1020, 950, 870, 850, 790, 750, 700, 630 cm ; H NMR (80 MHz, DMSO) δ 3.0–3.4
(m, 2H), 3.71 (s, 3H), 4.15–4.51 (m, 1H), 7.0–7.5 (m, 5H), 8.46 (broad s, 3H).
+
−
3
.19. (R)-(−) and (S)-(+) enantiomers of PhGlyNH ClO 21
3 4
The (R)-(−) and (S)-(+) enantiomers of 21 were prepared in the same way as described for (R)-(+) and
23
(
S)-(−)-20, starting from 2.00 g (13.23 mmol) of (R)-(−) and (S)-(+) methyl phenylglycinate. Pure (R)-
(
−) and (S)-(+) enantiomers of 21 were obtained by recrystallization from a MeOH–CHCl mixture.
3
Yields were 2.97 g (84%) for (R)-21 and 3.07 g (87%) for (S)-21; R =0.4 (silica TLC, 4% MeOH
f
2
5
in CH Cl ); (R)-(−)-21, mp: 118–119°C; [α] =−90.4 (c 1.0, ethanol); (S)-(+)- 21, mp: 120–121°C;
2
2
365
2
5
[
α] =+89.85 (c 1.0, ethanol); IR (KBr) ν 3180, 3120, 3110, 3080, 3000, 2810, 2680, 2600, 2000, 1720,
D
−1
1
600, 1500, 1460, 1430, 1370, 1300, 1150, 1120, 1100, 1030, 1020, 980, 870, 850, 740, 710, 640 cm ;
1
H NMR (80 MHz, DMSO) δ 3.73 (s, 3H), 5.31 (s, 1H), 7.5 (s, 5H), 8.92 (broad s, 3H).
3.20. General procedure for separation of racemic ammonium salts 18–21
The racemic salt (the amount is indicated in Table 2) was dissolved in 2 mL of the eluent (see Table 2)
and was placed onto the top of a column containing 48.0 g of (R,R)-6 and eluted with the MeOH–CH Cl2
2
mixture (see Table 2). The amount of salt was weighed in each 4 mL fraction after evaporation of the
solvent. Then the dry salt was dissolved in such a volume of methanol that the concentration of the
solution was about 5 mg/mL and the optical rotation was measured. Earlier, a calibration curve was
made using methanol as a solvent and the amounts of the enantiomers were calculated relying upon this
curve.
The calculated concentrations of (R)-(18–21) and (S)-(18–21) were plotted versus the mL of eluents
as shown in the smooth surfaces in Figs. 2–5.
Acknowledgements
Financial support by the Hungarian Scientific Research Fund (OTKA T-14942 and T-25071) and the
Office of Naval Research (USA) is gratefully acknowledged.

Z. Köntös et al. / Tetrahedron: Asymmetry 10 (1999) 2087–2099
2099
Table 2
Conditions for chromatographic separation of racemic ammonium salts
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