Enantiomerically pure chiral pyridino-crown ethers: Synthesis and enantioselectivity toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate

Article abstract of DOI:10.1016/S0957-4166(99)00381-X

Seven new enantiomerically pure chiral pyridino-crown ethers (S,S)-4- (R,R)-10 were prepared. Three of them [(S,S)-4, (S,S)-7 and (R,R)-10] contain one, and two of them [(S,S)-5 and (S,S)-8] contain two linker chains with a terminal double bond. These lin

Full text of DOI:10.1016/S0957-4166(99)00381-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3615–3626
Enantiomerically pure chiral pyridino-crown ethers: synthesis
and enantioselectivity toward the enantiomers of
α-(1-naphthyl)ethylammonium perchlorate†
Erika Samu,a Péter Huszthy,b,∗ György Horváth,a Áron Szöllo˝sy c and András Neszmélyi d
aInstitute for Organic Chemistry, Technical University of Budapest, H-1521 Budapest, Hungary
bResearch Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
cInstitute for General and Analytical Chemistry, Technical University of Budapest, H-1521 Budapest, Hungary
dCentral Research Institute for Chemistry, Hungarian Academy of Sciences, H-1525 Budapest, Hungary
Received 8 August 1999; accepted 31 August 1999
Abstract
Seven new enantiomerically pure chiral pyridino-crown ethers (S,S)-4–(R,R)-10 were prepared. Three of them
[(S,S)-4, (S,S)-7 and (R,R)-10] contain one, and two of them [(S,S)-5 and (S,S)-8] contain two linker chains with a
terminal double bond. These linker chains were connected to the carbon atom at position 9 (opposite the pyridine
moiety) of the macrocycle. The terminal double bond of the linker makes it possible to attach these ligands to silica
gel to obtain chiral stationary phases (CSPs). The enantioselectivity of the new ligands toward the enantiomers of
1
α-(1-naphthyl)ethylammonium perchlorate (NEA) was also determined by a titration H NMR method. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
The important role of enantiodiscrimination with respect to biological regulation and activity pheno-
mena, drug development, food and cosmetic industries, environmental and toxicity issues, stereoselective
synthesis, sensing and separating of enantiomers, etc. has been increasingly recognized over the past
years. In this context, a lot of attention has been devoted to the synthesis and evaluation of the enan-
tioselectivity of artificial chiral receptors (hosts) with the aim of using them for the discrimination of
enantiomers of chiral guest molecules.1,2 Enantiomerically pure chiral macrocycles, for example, have
proved to be very useful synthetic hosts for discriminating the enantiomers of chiral organic ammonium
salt guest molecules.3 Among these chiral macrocycles a number of chiral crown ethers containing
∗
†
Corresponding author. E-mail: huszthy.szk@chem.bme.hu
Dedicated to Professor Károly Lempert on the occasion of his 75th birthday.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00381-X

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
pyridine subcyclic units have been prepared.4–9 The enantioselectivity of chiral pyridino-18-crown-6
ligands toward the enantiomers of organic ammonium salts has been extensively studied.3,5–12 These
studies have established a tripod-like hydrogen bonding involving the pyridine nitrogen and two alternate
oxygen atoms of the pyridino-crown ether and the three ammonium protons of the organic salt (attractive
interaction), π–π stacking between the aromatic rings of the host and the guest (attractive interaction)
as well as the steric repulsion caused by the substituent at the stereogenic center of the ligand and
certain hydrogens of the ammonium salt (repulsive interaction), respectively.3,5–12 Recently we turned
our attention to the application of enantiopure chiral pyridino-18-crown-6 ligands in the separation of the
enantiomers of selected chiral organic ammonium salts.12–14 We have found that the enantioselectivity
characterized in homogeneous solution by ∆logK values, which were measured by a 1H NMR titration
method,15 paralleled very well with the effectiveness of the enantioseparation on the chiral stationary
phases (CSPs) prepared by attaching the chiral pyridino-host molecules covalently to silica gel12–14 (K is
the equilibrium constant for complex formation between one enantiomer of the chiral organic ammonium
salt and the chiral pyridino-crown host, ∆logK=logKheterochiral complex−logKhomochiral complex, heterochiral
complex: (R,R)-host/(S)-guest complex or (S,S)-host/(R)-guest complex, homochiral complex: (R,R)-
host/(R)-guest complex or (S,S)-host/(S)-guest complex).
In all cases, the tether which connected the chiral selector to the silica gel solid support was attached to
position 4 of the pyridine ring, thus the starting material for the preparation of the CSP was either crown
ether (S,S)-3 (see Fig. 1) or its analog differing only in the length of the linker and/or the substituent at
the stereogenic center.12–14
Figure 1. Chemical formulas of enantiomerically pure chiral pyridino-crown ethers
The immobilization of the chiral pyridino-crown ethers to the solid support by covalent Si–O–Si
bonds was carried out by firstly reacting the terminal double bond with triethoxysilane in the presence
of a Pt-catalyst, followed by heating the triethoxysilyl-derivative of the chiral ligand with silica gel in
toluene.12–14
With the aim of improving enantioseparation using enantiopure pyridino-crown ethers as chiral
selectors for silica gel-bound CSPs, we attached the linker(s) containing the terminal double bond to
position 9 of the carba-analogs of crown ethers (S,S)-2, (S,S)-6 and (R,R)-9 to obtain ligands (S,S)-4,
(S,S)-5, (S,S)-7, (S,S)-8 and (R,R)-10 (see Fig. 1).

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3617
The use of the latter chiral pyridino-crown ether ligands as chiral selectors instead of (S,S)-3 and
its analogs seems to be advantageous, because these macrocycles can be attached to the solid support
further from the pyridine ring and the stereogenic centers, so the interference of the Si-OH groups of the
silica gel becomes less pronounced with this portion of the macrocycle which is responsible mainly for
the enantioselectivity. It is worth mentioning here that the X-ray structures of the solid diastereomeric
complexes (R)-NEA–(S,S)-1 and (S)-NEA–(S,S)-1 clearly show that in the tripod-like hydrogen bonding
the macrocycle oxygen atom at position 9 is not involved,16 so crown ethers such as (S,S)-4, (S,S)-5, (S,S)-
7, (S,S)-8 and (R,R)-10 with no heteroatom in that position could form the above mentioned hydrogen
bonding.
In this paper, we report the synthesis of novel chiral macrocycles (S,S)-4, (S,S)-5, (S,S)-6, (S,S)-7,
(S,S)-8, (R,R)-9 and (R,R)-10 and also their enantiomeric recognition data (∆logK) for the enantiomers
1
of α-(1-naphthyl)ethylammonium perchlorate (NEA) determined by a H NMR titration method15 in
homogeneous solution (CD3OD:CDCl3 1:1). The cheapest and easiest obtainable ligand (S,S)-4 is
planned to attach covalently to silica gel by the usual method,12–14 and the CSP so prepared will be
tested for the enantioseparation of racemic organic ammonium salts by chromatography. These studies
will be reported in a future publication.
2. Results and discussion
Enantiomerically pure (S,S)-dimethyldiketopyridino-18-crown-6 ligand (S,S)-117 and (S,S)-
dimethylpyridino-18-crown-6 ligand (S,S)-211 were prepared as reported. New enantiomerically
pure chiral pyridino-crown ethers (S,S)-4–(R,R)-10 were prepared as shown in Scheme 1.
Scheme 1. Preparation of new enantiopure chiral ligands
The structures proposed for these new macrocycles are consistent with data obtained from 1H and 13
C
NMR, mass and IR spectra and elemental analyses. The yields for the Williamson-type macrocyclic ether
formation reaction using the strong base NaH and THF as a solvent were in the 45–69% range. We should
mention here that the syntheses of (R,R)-66 and (S,S)-9,7 the antipodes of (S,S)-6 and (R,R)-9, have been
reported.
Diols (S,S)-11,18 (S,S)-12,18 (S,S)-14,18 (S,S)-1518 and tetraethylene glycol (R,R)-1614 were obtained
as described in the literature. The chiral diisobutyl-substituted tetraethylene glycol (S,S)-13 needed for
the preparation of macrocycle (S,S)-6 was obtained as shown in Scheme 2.
Hydroxy acid (S)-19 was treated with an excess of dihydropyran (DHP) in the presence of pyridinium
p-toluenesulfonate (PPTS) catalyst to obtain bis(THP)-derivative (S)-20 which was reduced to THP-
protected glycol (S)-21. Two moles of the monosodium salt of alcohol (S)-21 were reacted with one mole
of diethylene glycol ditosylate 22 followed by deblocking the THP protecting groups to give tetraethylene

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
Scheme 2. Preparation of new enantiomerically pure diisobutyl-substituted tetraethylene glycol (S,S)-13
glycol (S,S)-13. Enantiomerically pure di-tert-butyl-substituted diol (R,R)-17 needed for the preparation
of chiral ligand (R,R)-10 was obtained as shown in Scheme 3.
Scheme 3. Preparation of new enantiopure di-tert-butyl-substituted diol (R,R)-17 containing a side chain with a terminal double
bond
One mole of allyl-substituted-pentan-1,5-diol 2318 was treated first with an excess of strong base KOt-
Bu, then the resulting dialkoxide was reacted with two moles of (R)-24a and/or (R)-24b (see Scheme 3)
followed by deblocking the THP protecting groups to give chiral diol (R,R)-17. It is interesting that the
two diastereomeric diols (R)-25a and (R)-25b behave very differently in certain tosylation reactions as
shown in Scheme 4.
When the mixture of (R)-25a and (R)-25b was treated with tosyl chloride using powdered KOH
as a base in THF, only one of the diastereomers [(R)-25a] reacted and the other [(R)-25b] remained
intact. Using pyridine as a base and a solvent both diastereomeric alcohols (R)-25a and (R)-25b were
transformed to tosylates (R)-24a and (R)-24b. Tosylate(s) (R)-24a and/or (R)-24b resulted in the same
tert-butyl-substituted glycol monotosylate (R)-26 by deblocking the THP protecting group with the help
of ion-exchange resin (H+ form) in methanol.
Pyridino-18-crown 6 ligands are appropriate hosts for primary ammonium salts like NEA.3 The chiral
hosts form complexes of different equilibrium constants with the two enantiomers of NEA so that the
difference in logK values could serve as a parameter referring to the enantioselectivity of a ligand. The
1
equilibrium constants were determined by the H NMR titration method originally described by Zhu
1
et al.15 Adding small quantities of NEA (guest) to the solution of a ligand (host) and taking H NMR
spectra after each charge induce shifts of selected signals. The induced shift (δi) is a function of the molar
ratio (ρ=guest/host), the actual equilibrium constant (K) as well as the shift which could be measured
in the case of complex (δc) (the complex is formed by one host and one guest molecule).15 With a
known starting concentration the molar ratios were determined by the integration of the NMR spectra.
The equilibrium constant and the chemical shift of the complex were determined by a two-parameter
nonlinear regression fit. Although complexation induces shifts at several signals of the host, and these

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3619
Scheme 4. Tosylation of diastereomeric diols (R)-25a and (R)-25b and deblocking the THP protecting group of the tosylates
(R)-24a and (R)-24b
shifts can be used for calculation, the best results could be achieved by monitoring those signals where
the induced shifts are quite large (δi>0.1 ppm).
Reliability of our measurements and calculations were checked by comparison of our data for (S,S)-1
and (S,S)-2 with those reported for (S,S)-111 and (S,S)-219 earlier in the literature.
The logK and ∆logK values shown in Table 1 are in accord with the generally observed heterochiral
preference for the interactions between the pyridino-crown ethers and the enantiomers of NEA.3,10,11
Table 1
Enantiomeric recognition data (∆logK) determined by the 1H NMR titration method in homogeneous
solution (CD3OD:CDCl3 1:1) for the enantiomer pairs of NEA with chiral pyridine-containing
macrocycles at 298 K
The two exceptions to this general observation are the homochiral preference of ligands (S,S)-
4 and (S,S)-7 containing one linker chain. It can also be seen from the data in Table 1, that the
presence of one linker chain decreases the enantioselectivity only to a very small extent, while the
incorporation of two linker chains results in a more significant decrease in ∆logK values. This tendency in
enantioselectivity was also observed in the case of analogous phenazino-crown ethers when one and two

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
of the same linker chains were incorporated in similar positions of the macrocycle as shown by circular
dichroism spectroscopy.18 Thus (S,S)-4, (S,S)-7 and (R,R)-9 are all suitable selectors for chromatographic
enantioseparation of racemic NEA and probably other racemic organic ammonium salts as well.
3. Experimental
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
enantiomers of menthol. H (500 MHz) and 13C (125 MHz) NMR spectra were recorded on a Bruker
1
DRX-500 Avance spectrometer and H (80 MHz) NMR spectra were obtained on a Bruker AW-80
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 determined 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 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 well established methods.20 Evaporations
were carried out under reduced pressure unless otherwise stated.
For determination of logK values ligands (S,S)-4 -(R,R)-10 were dissolved in CDCl3:CD3OD (1:1;
v/v). The NMR spectra were recorded at 298 K on a Bruker DRX-500 Avance spectrometer. To enhance
the integral accuracy, 5 s delay time and 64 K zero filling were applied for recording the 1H NMR spectra.
3.1. (4S,14S)-(+)-4,14-Dimethyl-9-(2-propenyl)-3,6,12,15-tetraoxa-21-azabicyclo[15.3.1]heneicosa-
1(21),17,19-triene (S,S)-4
To a well stirred suspension of NaH (224 mg, 5.6 mmol, 60% dispersion in mineral oil) in THF (10
mL) was added dropwise under Ar at rt (2S,12S)-(+)-7-(2-propenyl)-4,10-dioxatridecane-2,12-diol (S,S)-
1118 (520 mg, 2 mmol) dissolved in THF (20 mL). The mixture was stirred at rt for 10 min and at reflux
temperature for 3 h. The reaction mixture was cooled to −60°C and ditosylate 186,21 (984 mg, 2.2 mmol)
dissolved in THF (20 mL) was added dropwise. The resulting mixture was stirred at −60°C for 20 min and
then at rt for 5 days. After the reaction was completed, the solvent was removed. The residue was taken
up in the mixture of ice-water (15 mL) and ether (50 mL). The resulting mixture was mixed well and
separated. The aqueous phase was shaken with ether (2×50 mL). The combined organic phase was dried
over MgSO4, filtered and the solvent evaporated. The crude product was purified by chromatography on
neutral alumina using 1% EtOH in toluene as an eluent to give pure (S,S)-4 (385 mg, 53%) as a clear
oil; Rf=0.33 (alumina TLC, 2% EtOH in toluene); [α]25 +23.8 (c 0.567, CH2Cl2); IR (neat) ν 3072,
D
3040, 2960, 2940, 2870, 2860, 1640, 1592, 1576, 1460, 1368, 1336, 1110, 1000, 912, 816, 760 cm−1;
1H NMR (500 MHz) δ 1.15 (d, J=7 Hz, 3H), 1.16 (d, J=7 Hz, 3H), 1.40–1.46 (m, 4H), 1.65–1.70 (m,
1H), 1.97–2.01 (m, 2H), 3.33–3.42 (m, 6H), 3.47–3.51 (m, 2H), 3.77–3.82 (m, 2H), 4.69–4.82 (m, 4H),
4.93–4.98 (m, 2H), 5.64–5.72 (m, 1H), 7.24 (d, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), (t, J=8 Hz, 1H); 13
C
NMR: (125 MHz) δ 17.60, 17.76, 31.37, 33.95, 34.05, 38.36, 69.35, 69.94, 72.16, 72.68, 73.86, 74.55,
75.98, 76.00, 116.62, 120.93, 120.97, 137.01, 137.20, 158.62, 158.89; HRMS (EI) calcd for C21H33NO4:
363.2410, found: 363.2397. Anal. calcd for C21H33NO4: C, 69.38; H, 9.16; N, 3.86; found: C, 69.20; H,
9.36; N, 3.95.

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3621
3.2. (4S,14S)-(+)-4,14-Dimethyl-9,9-bis(2-propenyl)-3,6,12,15-tetraoxa-21-azabicyclo[15.3.1]henei-
cosa-1(21),17,19-triene (S,S)-5
Macrocycle (S,S)-5 was prepared as described above for macrocycle (S,S)-4 starting from (2S,12S)-
(+)-7,7-bis(2-propenyl)-4,10-dioxatridecane-2,12-diol (S,S)-1218 (600 mg, 2 mmol) and ditosylate 18
(984 mg, 2.2 mmol). The reaction was completed at rt in 6 days. The crude product was purified by
chromatography on neutral alumina using 1% EtOH in toluene as an eluent to give pure (S,S)-5 (412 mg,
51%) as a clear oil; Rf=0.39 (alumina TLC, 2% EtOH in toluene); [α]25 +20.6 (c 2.08, CH2Cl2); IR
D
(neat) ν 3072, 3040, 2976, 2960, 2928, 2860, 1640, 1592, 1576, 1560, 1456, 1376, 1336, 1264, 1116,
1000, 912, 816, 760 cm−1; 1H NMR (500 MHz) δ 1.18 (d, J=7 Hz, 6H), 1.42–1.48 (m, 4H), 1.94 (d, J=7
Hz, 4H), 3.35–3.45 (m, 8H), 3.77–3.83 (m, 2H), the benzylic -CH2- gives an AB spin system: δA 4.69,
δB 4.81, (JAB=13 Hz, 4H), 4.98–5.04 (m, 4H), 5.72–5.80 (m, 2H), 7.30 (d, J=8 Hz, 2H), 7.67 (t, J=8
Hz, 1H); 13C NMR (125 MHz) δ 17.60, 36.47, 37.24, 42.11, 67.60, 72.27, 74.22, 75.38, 117.74, 121.12,
134.69, 137.11, 158.49; HRMS (EI) calcd for C24H37NO4: 403.2723, found: 403.2730. Anal. calcd for
C24H37NO4: C, 71.42; H, 9.25; N, 3.47; found: C, 71.31; H, 9.04; N, 3.71.
3.3. (4S,14S)-(−)-4,14-Diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-
triene (S,S)-6
Macrocycle (S,S)-6 was prepared as described above for macrocycle (S,S)-4 starting from (4S,14S)-(−)-
2,16-dimethyl-6,9,12-trioxaheptadecane-4,14-diol (S,S)-13 (613 mg, 2 mmol) and ditosylate 18 (984 mg,
2.2 mmol). The reaction was completed at rt in 4 days. The crude product was purified by chromatography
on neutral alumina using 1% EtOH in toluene as an eluent to give pure (S,S)-6 (369 mg, 45%) as a clear
oil; [α]25 −2.1 (c 1.04, CH2Cl2); [α]25 −3.9 (c 0.204, CHCl3), lit.6 [α]25 +2.97 (c 0.204, CHCl3) for the
D
D
D
other enantiomer (R,R)-6. All other physical properties and spectral data were identical to those reported6
for (R,R)-6.
3.4. (4S,14S)-(−)-4,14-Diisobutyl-9-(2-propenyl)-3,6,12,15-tetraoxa-21-azabicyclo[15.3.1]heneicosa-
1(21),17,19-triene (S,S)-7
Macrocycle (S,S)-7 was prepared as described above for macrocycle (S,S)-4 starting from (4S,14S)-
(+)-2,16-dimethyl-9-(2-propenyl)-6,12-dioxaheptadecane-4,14-diol (S,S)-1418 (689 mg, 2 mmol) and
ditosylate 18 (984 mg, 2.2 mmol). The reaction was completed at rt in 5 days. The crude product was
purified by chromatography on neutral alumina using 0.7% EtOH in toluene as an eluent to give pure
(S,S)-7 (528 mg, 59%) as a clear oil; Rf=0.61 (alumina TLC, 2% EtOH in toluene); [α]25 −10.6 (c
D
0.404, CH2Cl2); IR (neat) ν 3072, 3040, 2960, 2928, 2860, 1640, 1592, 1576, 1460, 1368, 1320, 1120,
992, 912, 816, 760 cm−1; 1H NMR (500 MHz) δ 0.87 (d, J=7 Hz, 6H), 0.91 (d, J=7 Hz, 3H), 0.93 (d, J=7
Hz, 3H), 1.17–1.22 (m, 2H), 1.44–1.54 (m, 6H), 1.65–1.72 (m, 1H), 1.75–1.81 (m, 2H), 2.00–2.04 (m,
2H), 3.39–3.53 (m, 8H), 3.67–3.72 (m, 2H), 4.79–4.85 (m, 4H), 4.96–5.00 (m, 2H), 5.67–5.76 (m, 1H),
7.31 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.68 (t, J=8 Hz, 1H); 13C NMR (125 MHz) δ 22.26, 23.38,
24.59, 31.02, 33.44, 33.71, 37.95, 41.10, 41.24, 69.00, 69.68, 72.14, 72.51, 74.76, 74.91, 75.75, 76.27,
116.25, 120.59, 136.55, 136.99, 158.20, 158.31; HRMS (EI) calcd for C27H45NO4: 447.3349, found:
447.3357. Anal. calcd for C27H45NO4: C, 72.43; H, 10.14; N, 3.13; found: C, 72.24; H, 10.08; N, 3.15.

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3.5. (4S,14S)-(−)-4,14-Diisobutyl-9,9-bis(2-propenyl)-3,6,12,15-tetraoxa-21-azabicyclo[15.3.1]henei-
cosa-1(21),17,19-triene (S,S)-8
Macrocycle (S,S)-8 was prepared as described above for macrocycle (S,S)-4 starting from (4S,14S)-(+)-
2,16-dimethyl-9,9-bis(2-propenyl)-6,12-dioxaheptadecane-4,14-diol (S,S)-1518 (769 mg, 2 mmol) and
ditosylate 18 (984 mg, 2.2 mmol). The reaction was completed at rt in 6 days. The crude product was
purified by chromatography on neutral alumina using 0.5% EtOH in toluene as an eluent to give pure
(S,S)-8 (468 mg, 48%) as a clear oil; Rf =0.70 (alumina TLC, 2% EtOH in toluene); [α]25 −10.6 (c
D
1.04, CH2Cl2); IR (neat) ν 3072, 3040, 2952, 2928, 2888, 2872, 1640, 1592, 1576, 1460, 1368, 1336,
1
1260, 1116, 996, 912, 816, 760 cm−1; H NMR (500 MHz) δ 0.85 (d, J=7 Hz, 6H), 0.91 (d, J=7 Hz,
6H), 1.17–1.22 (m, 2H), 1.42–1.52 (m, 6H), 1.74–1.79 (m, 2H), 1.94 (d, J=7 Hz, 4H), 3.36–3.46 (m,
8H), 3.67–3.71 (m, 2H), the benzylic -CH2- gives an AB spin system: δA 4.74, δB 4.79, (JAB=13 Hz,
4H), 4.97–5.03 (m, 4H), 5.72–5.80 (m, 2H), 7.31 (d, J=8 Hz, 2H), 7.67 (t, J=8 Hz, 1H); 13C NMR (125
MHz) δ 22.61, 23.84, 24.94, 36.67, 37.42, 41.72, 42.34, 67.88, 72.97, 74.92, 76.59, 118.01, 121.30,
134.87, 137.34, 158.72; HRMS (EI) calcd for C30H49NO4: 487.3662, found: 487.3667. Anal. calcd for
C30H49NO4: C, 73.87; H, 10.13; N, 2.87; found: C, 74.02; H, 9.88; N, 3.09.
3.6. (4R,14R)-(+)-4,14-Di-tert-butyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,
19-triene (R,R)-9
Macrocycle (R,R)-9 was prepared as described above for macrocycle (S,S)-4 starting from (3R,13R)-
(−)-2,2,14,14-tetramethyl-5,8,11-trioxapentadecane-3,13-diol (R,R)-1614 (613 mg, 2 mmol) and ditosyl-
ate 18 (984 mg, 2.2 mmol). The reaction was completed at rt in 4 days. The crude product was purified
by chromatography on neutral alumina using 0.5% EtOH in toluene as an eluent to give pure (R,R)-9
(565 mg, 69%) as a clear oil; [α]25 +11.3 (c 1.01, CH2Cl2), [α]25 +15.1 (c 0.425, benzene), lit.7 [α]25
D
D
D
−15.09 (c 0.424, benzene) for the other enantiomer (S,S)-9. All other physical properties and spectral
data were identical to those reported7 for (S,S)-9.
3.7. (4R,14R)-(+)-4,14-Di-tert-butyl-9-(2-propenyl)-3,6,12,15-tetraoxa-21-azabicyclo[15.3.1]henei-
cosa-1(21),17,19-triene (R,R)-10
Macrocycle (R,R)-10 was prepared as described above for macrocycle (S,S)-4 starting from (3R,13R)-
(−)-2,2,14,14-tetramethyl-8-(2-propenyl)-5,11-dioxapentadecane-3,13-diol (R,R)-17 (689 mg, 2 mmol)
and ditosylate 18 (984 mg, 2.2 mmol). The reaction was completed at rt in 6 days. The crude product
was purified by chromatography on neutral alumina using 0.4% EtOH in toluene as an eluent to give
pure (R,R)-10 (457 mg, 51%) as a clear oil; Rf=0.81 (alumina TLC, 2% EtOH in toluene); [α]25 +20.8
D
(c 2.48, CH2Cl2); IR (neat) ν 3072, 3040, 2952, 2920, 2888, 2864, 1640, 1592, 1576, 1480, 1460, 1360,
1336, 1112, 992, 912, 800, 760 cm−1; 1H NMR (500 MHz) δ 0.97 (s, 9H), 0.99 (s, 9H), 1.35–1.53 (m,
4H), 1.71–1.78 (m, 1H), 1.99–2.09 (m, 2H), 3.21–3.23 (m, 1H), 3.26–3.28 (m, 1H), 3.40–3.53 (m, 6H),
3.68–3.72 (m, 2H), 4.84–4.92 (m, 4H), 5.00–5.04 (m, 2H), 5.71–5.79 (m, 1H), 7.35 (d, J=8 Hz, 1H), 7.38
(d, J=8 Hz, 1H), 7.70 (t, J=8 Hz, 1H); 13C NMR (125 MHz) δ 26.57, 26.61, 31.23, 33.67, 34.31, 34.73,
34.75, 37.93, 69.02, 69.99, 72.30, 72.82, 74.38, 74.70, 85.35, 85.80, 116.41, 120.53, 120.81, 136.82,
136.84, 158.37, 158.67; HRMS (EI) calcd for C27H45NO4: 447.3349, found: 447.3344. Anal. calcd for
C27H45NO4: C, 72.43; H, 10.14; N, 3.13; found: C, 72.28; H, 10.03; N, 3.24.

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3623
3.8. (4S,14S)-(−)-2,16-Dimethyl-6,9,12-trioxaheptadecane-4,14-diol (S,S)-13
To a well stirred suspension of NaH (5.11 g, 153 mmol, 60% dispersion in mineral oil) in THF (30 mL)
was added dropwise at 0°C and under Ar (S)-(−)-4-methyl-2[(tetrahydro-2H-pyran-2-yl)oxy]-pentan-1-
ol [(S)-21, see Section 3.11] (21.7 g, 107 mmol) dissolved in THF (145 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 22 (20.9 g, 50 mmol) dissolved in THF (75 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 (50 g), water (100 mL) and ether (300 mL). The mixture
was shaken well and separated. The aqueous phase was extracted with ether (2×100 mL). The combined
organic phase was shaken with saturated brine (200 mL), dried over MgSO4, filtered and the solvent was
evaporated. The residue (28 g) was dissolved in MeOH (500 mL) and Amberlite® IR-120 strong acidic
ion-exchange resin (H+ form) (4 g) was added to this solution. After stirring the mixture at rt for 1 day, the
resin was filtered off and washed with MeOH (3×30 mL). The filtrate and washings were combined and
the solvent evaporated. The residue was taken up in a mixture of water (40 mL), methanol (200 mL) and
hexane (60 mL). The mixture was shaken well and separated. The aqueous methanol phase was extracted
with hexane (3×60 mL). The combined hexane phase was shaken with 20% water in methanol (120
mL). The combined aqueous methanol solution was evaporated. The residue was dissolved in toluene
and the solvent was removed. The latter procedure was repeated twice to remove traces of water. The
crude product was purified by distillation to give (S,S)-13 (10.1 g, 65%) as a clear oil; bp: 125–136°C
(0.1 mmHg); Rf=0.50 (silica TLC 9% EtOH in toluene); [α]25 +9.6 (c 0.101, CHCl3), lit.6 [α]25 −8.57
D
D
(c 0.103, CHCl3) for the other enantiomer (R,R)-13. All other physical properties and spectral data were
identical to those reported6 for (R,R)-13.
3.9. (3R,13R)-(−)-2,2,14,14-Tetramethyl-8-(2-propenyl)-5,11-dioxapentadecane-3,13-diol (R,R)-17
To a well stirred mixture of KOt-Bu (2.69 g, 0.024 mol) and HMPA (30 mL) was added in an ice-
water bath and under Ar 3-(2-propenyl)-pentan-1,5-diol 2318 (865 g, 6 mmol). The reaction mixture
was stirred in an ice-water bath for 5 min then (R)-(−)-3,3-dimethyl-2[(tetrahydro-2H-pyran-2-yl)oxy]-
butan-1-ol p-tosylate [(R)-24a and/or (R)-24b, see below] (8.56 g, 24 mmol) was added and stirring was
continued in the ice-water bath for 4 h and at rt for 1 day. The resulting mixture was taken up in ice-water
(100 mL) and ether (200 mL). The aqueous phase was extracted with ether (3×120 mL). The combined
organic phase was shaken with ice cold water (500 mL), saturated brine (250 mL), dried over MgSO4,
filtered and evaporated. The residue (4 g) was dissolved in MeOH (50 mL) and Amberlite® IR-120 strong
acidic ion-exchange resin (H+ form) (0.5 g) was added to this solution. After stirring the mixture at rt
for 1 day, the resin was filtered off and washed with MeOH (3×5 mL). The filtrate and washings were
combined and the solvent evaporated. The residue was dissolved in toluene and the solvent was removed.
The latter procedure was repeated twice to remove traces of water. The crude product was purified by
chromatography on silica gel using 6% acetone in CH2Cl2 as an eluent to give (R,R)-17 (393–475 mg,
19–23%) as a colorless oil. Rf=0.52 (silica gel TLC, 14% acetone in CH2Cl2); [α]25 −28.9 (c 1.44,
D
CH2Cl2); IR (neat) ν 3580–3220 (broad), 3080, 3048, 2960, 2910, 2870, 1640, 1480, 1460, 1384, 1368,
1
1324, 1184, 1116, 1080, 1016, 916, 760 cm−1; H NMR (500 MHz) δ 0.92 (s, 18H), 1.56–1.64 (m,
4H), 1.74–1.80 (m, 1H), 2.05–2.08 (m, 2H), 2.83 (broad s, 2H), 3.25–3.32 (m, 2H), 3.43–3.59 (m, 8H),
5.01–5.04 (m, 2H), 5.72–5.80 (m, 1H); 13C NMR (125 MHz) δ 26.23, 31.89, 33.46, 33.50, 33.62, 38.85,
69.31, 69.63, 72.19, 72.36, 76.97, 77.36, 116.66, 136.86.

3624
E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3.10. (S)-(−)-(Tetrahydro-2H-pyran-2-yl) 2-[(tetrahydro-2H-pyran-2-yl)oxy]-4-methylpentanoate (S)-
20
To a well stirred mixture of hydroxy acid (S)-19 (29.6 g, 0.224 mol), dihydropyran (DHP) (63.2 mL,
58 g, 0.69 mol) and pure and dry CH2Cl2 (60 mL) was added in an ice–salt bath and under Ar pyridinium
p-toluenesulfonate (PPTS) catalyst (2.2 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, CH2Cl2 (300 mL) was added. The resulting mixture
was shaken with 5% NaHCO3 (100 mL) and water (2×100 mL). The organic phase was dried over
MgSO4, filtered and the solvent was removed to give crude (S)-20 (65.6 g, 98%) as a mixture of four
diastereomers, which was used without further purification; Rf=0.7, 0.8, 0.9 (silica gel TLC 20% 2-
butanone in toluene); [α]25 −5.1 (c 1.21, CH2Cl2); IR (neat) ν 3080, 3030, 2960, 2930, 2870, 1750,
D
1468, 1424, 1380, 1360, 1320, 1296, 1270, 1250, 1185, 1120, 1080, 1024, 984, 928, 904, 870, 812, 752
cm−1; 1H NMR (80 MHz) δ 0.90 (d, J=6 Hz, 6H), 1.2–2.1 (m, 15H), 3.3–4.1 (m, 5H), 4.5–4.7 (m, 1H),
5.9–6.1 (m, 1H).
3.11. (S)-(−)-4-Methyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]-pentan-1-ol (S)-21
To a well stirred suspension of LiAlH4 (9.6 g, 0.25 mol) in ether (80 mL) was slowly added crude
(S)-20 (65.6 g, 0.22 mol) dissolved in ether (90 mL) under Ar at 0°C. The mixture was stirred at 0°C for
30 min, at rt for 1 day, and at reflux temperature for 48 h. When the reduction was completed, the mixture
was cooled in an ice–salt bath and first saturated NH4Cl (10 mL) then 5% NaOH solution (20 mL) 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 combined ethereal
solution was shaken with saturated brine, dried over MgSO4, filtered and the solvent evaporated. The
crude product was purified by distillation to give (S)-21 (33 g, 73%) as a mixture of two diastereomers;
bp: 72–76°C (0.1 mmHg); Rf=0.25, 0.35 (silica TLC 20% EtOAc in toluene); [α]25 −20.1 (c 1.91,
D
CH2Cl2); IR (neat) ν 3620–3220 (broad), 3080, 3050, 3030, 2960, 2930, 2882, 2876, 1468, 1424, 1380,
1360, 1272, 1198, 1185, 1144, 1088, 1024, 984, 888, 816 cm−1; 1H NMR (80 MHz) δ 0.9 (d, J=6 Hz,
6H), 1.1–2.0 (m, 9H), 2.4 (broad s, disappeared with D2O, 1H), 3.3–4.2 (m, 5H), 4.7–4.9 (m, 1H).
3.12. (R)-(+)-3,3-Dimethyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]-butan-1-ol p-tosylate (R)-24a (first dia-
stereomer)
To a well stirred mixture of finely powdered KOH (8.71 g, 85%, 132 mmol) in THF (30 mL) was added
dropwise at −20°C and under Ar first a mixture of alcohol (R)-25a and (R)-25b14 (6.65 g, 33 mmol)
dissolved in THF (40 mL), then tosyl chloride (8.8 g, 46 mmol) dissolved in THF (40 mL). The resulting
mixture was stirred at −20°C for 2 h, then it was allowed to warm up to rt and stirring was continued at rt
for 1 day. The solvent was evaporated at rt, and the residue was taken up in ice-water (75 mL) and CH2Cl2
(150 mL). The aqueous phase was extracted with CH2Cl2 (3×75 mL). The combined organic phase was
shaken with distilled water (200 mL), dried over MgSO4, filtered and evaporated. The crude material was
purified first by chromatography on silica gel using 10% EtOAc in hexane as an eluent, then triturating
the product with hexane to give (R)-24a (5.18 g, 48%, one of the two diastereomers) as white crystals.
Mp: 52°C (hexane); Rf=0.50 (silica gel TLC, 20% EtOAc in hexane); [α]25 +34.1 (c 4.51, CH2Cl2); IR
D
(KBr) ν 3080, 3030, 2960, 2930, 2870, 1600, 1492, 1475, 1456, 1395, 1364, 1185, 1176, 1144, 1088,
1028, 960, 904, 816, 752, 688, 664, 552 cm−1; 1H NMR (500 MHz) δ 0.92 (s, 9H), 1.44–1.51 (m, 4H),
1.59–1.64 (m, 1H), 1.73–1.79 (m, 1H), 2.46 (s, 3H), 3.42–3.47 (m, 1H), 3.54–3.57 (m, 1H), 3.87–3.92

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
3625
(m, 1H), 3.99–4.04 (m, 1H), 4.25–4.29 (m, 1H), 4.66–4.69 (m, 1H), 7.36 (d, J=8 Hz, 2H), 7.80 (d, J=8
Hz, 2H); 13C NMR (125 MHz) δ 20.06, 21.55, 25.28, 26.41, 30.97, 34.01, 63.40, 71.17, 80.80, 98.77,
127.76, 129.78, 132.92, 144.77.
The other starting diastereomer alcohol (R)-25b was recovered in 46% yield (3.2 g). Rf=0.35 (silica
gel TLC, 20% EtOAc in hexane); [α]25 −62.5 (c 0.510, CH2Cl2); IR (KBr) ν 3080, 3030, 2960, 2930,
D
2870, 1600, 1492, 1475, 1456, 1395, 1364, 1185, 1176, 1144, 1088, 1028, 960, 904, 816, 752, 688, 664,
1
552 cm−1; H NMR (500 MHz) δ 0.90 (s, 9H), 1.48–1.56 (m, 4H), 1.82–1.86 (m, 2H), 3.20 (broad s,
1H), 3.47–3.54 (m, 2H), 3.66 (t, J=10 Hz, 1H), 4.02 (d, J=10 Hz, 1H), 4.10 (d, J=10 Hz, 1H), 4.35–4.37
(m, 1H); 13C NMR (125 MHz) δ 21.48, 24.91, 26.21, 31.11, 34.19, 62.25, 65.46, 92.20, 103.20.
3.13. (R)-(−)-3,3-Dimethyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]-butan-1-ol p-tosylate (R)-24b (second
diastereomer)
To a stirred solution of alcohol (R)-25b (3.2 g, 16 mmol, one of the two diastereomers) in pyridine
(10 mL) at rt and under Ar was added tosyl chloride (4.7 g, 24 mmol) dissolved in pyridine (5 mL). The
reaction mixture was stirred at rt for 1 day then it was poured into ice-water (150 mL). The aqueous
mixture was extracted with ether (2×150 mL). The combined organic phase was shaken with distilled
water (300 mL), saturated brine (150 mL), dried over MgSO4, filtered, and the solvent evaporated. The
rest of the pyridine was removed under strongly reduced pressure (0.2 mmHg). The crude product was
purified by chromatography on silica gel using 10% EtOAc in hexane as an eluent to give (R)-24b (5.1
g, 91%, one of the two diastereomers) which solidified after standing; mp: 38°C; Rf=0.45 (silica gel
TLC, 20% EtOAc in hexane); [α]25 −44.5 (c 4.61, CH2Cl2); IR (KBr) ν 3080, 3030, 2960, 2930, 2870,
D
1600, 1468, 1424, 1380, 1360, 1296, 1185, 1176, 1120, 1080, 1024, 984, 960, 928, 888, 840, 812, 744,
1
672, 648, 552, 504 cm−1; H NMR (500 MHz) δ 0.90 (s, 9H), 1.44–1.57 (m, 4H), 1.62–1.68 (m, 1H),
1.73–1.79 (m, 1H), 2.44 (s, 3H), 3.33–3.38 (m, 2H), 3.78–3.83 (m, 1H), 4.14–4.20 (m, 2H), 4.54–4.57
(m, 1H), 7.33 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 19.59, 21.54, 25.26, 25.72,
26.07, 30.58, 35.03, 62.57, 70.48, 84.12, 101.43, 127.99, 129.60, 132.97, 144.52.
3.14. Mixture of the two diastereomeric tosylates (R)-24a and (R)-24b
A mixture of the tosylates (R)-24a and (R)-24b was prepared as described above for tosylate (R)-24b
starting from a mixture of the alcohols (R)-25a and (R)-25b (10.1 g, 50 mmol). The crude product was
purified by chromatography on silica gel using 10% EtOAc in hexane as an eluent to give (R)-24a and
(R)-24b (15.8 g, 89%) which solidified after standing; mp: 34–36°C; Rf=0.45, 0.50 (silica gel TLC, 20%
EtOAc in hexane); [α]25 −9.4 (c 4.45, CH2Cl2). The IR, 1H NMR and 13C NMR spectra contained all
D
the spectral data of the two individual diastereomeric tosylates (R)-24a and (R)-24b. From the 1H NMR
spectrum of the mixture a ratio of 44:56 [(R)-24a]:[(R)-24b] for the two diastereomeric tosylates could
be calculated.
3.15. (R)-(−)-1-(Tosyloxy)-3,3-dimethyl-butan-2-ol (R)-26
Diastereomeric ditosylate (R)-24a or (R)-24b, or the mixture of the two (0.71 g, 2 mmol) was dissolved
in MeOH (10 mL) and Amberlite® IR-120 strong acidic ion-exchange resin (H+ form) (0.1 g) was added
to this solution. After stirring the mixture at rt for 1 day, the resin was filtered off and washed with
MeOH (3×5 mL). The filtrate and washings were combined and the solvent evaporated. The residue was
dissolved in toluene and the solvent was removed. The latter procedure was repeated twice to remove

3626
E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 3615–3626
traces of water. The crude product was purified by chromatography on silica gel using 10% EtOAc in
hexane as an eluent to give (R)-26 (0.51–0.52 g, 94–96%) as white crystals. According to their physical
and spectroscopical data in all three cases the same monotosylate (R)-26 was obtained; [α]25 +27.7 (c
D
1.12, benzene), lit.7 [α]25 −27.42 (c 1.098, benzene) for the other enantiomer (S)-26. All other physical
D
properties and spectral data were identical to those reported7 for (S)-26.
Acknowledgements
Financial support by the Hungarian Scientific Research Foundation (OTKA T-25071) is gratefully
acknowledged.
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