Enantiomerically pure chiral phenazino-crown ethers: Synthesis, preliminary circular dichroism spectroscopic studies and complexes with the enantiomers of 1-arethyl ammonium salts

Article abstract of DOI:10.1016/S0957-4166(99)00287-6

Enantiomerically pure chiral crown ethers containing the phenazine unit [(R,R)-2-(S,S)-8] were prepared by two types of cyclization reactions. Ligands (R,R)-2, (R,R)-3, (S,S)-4, (R,R)-5, (R,R)-6 and (R,R)-7 were prepared from phenazine-1,9-diol 9 and the

Full text of DOI:10.1016/S0957-4166(99)00287-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2775–2795
Enantiomerically pure chiral phenazino-crown ethers: synthesis,
preliminary circular dichroism spectroscopic studies and
complexes with the enantiomers of 1-arethyl ammonium salts
Erika Samu,a Péter Huszthy,b,∗ László Somogyi c and Miklós Hollósi c
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
cDepartment of Organic Chemistry, Eötvös Lorand University, H-1518 Budapest, Hungary
Received 21 June 1999; accepted 9 July 1999
Abstract
Enantiomerically pure chiral crown ethers containing the phenazine unit [(R,R)-2–(S,S)-8] were prepared
by two types of cyclization reactions. Ligands (R,R)-2, (R,R)-3, (S,S)-4, (R,R)-5, (R,R)-6 and (R,R)-7 were
prepared from phenazine-1,9-diol 9 and the appropriate ditosylates (S,S)-10–(S,S)-15 in weak basic conditions
with complete inversion of configuration. Ligands (S,S)-2, (S,S)-7 and (S,S)-8, however, were prepared from
1,9-dichlorophenazine 19 and the appropriate diols (S,S)-16–(S,S)-18 in strong basic conditions with retention
of configuration. Enantiomeric recognition of most of the chiral ligands with α-(1-naphthyl)ethylammonium
perchlorate (NEA) and α-phenylethylammoniumperchlorate (PEA) has been studied by CD spectroscopy. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
Since the first synthesis of crown ethers more than three decades ago1 the field of host–guest
chemistry2 has developed into the very active research area of supramolecular chemistry.3,4 Inside this
area, much effort has been devoted to the design, synthesis and study of synthetic chiral receptors capable
of enantioselective recognition of chiral guests.3,5
As model systems of enantiomeric recognition, such synthetic chiral receptors not only provide a
controlled means for studying the fundamentals of non-covalent intermolecular forces in nature, but also
open new routes for the development of novel pharmaceuticals, enantiomer-selective sensors, catalysts,
selectors and other molecular devices.3
∗
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)00287-6

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Our interest in enantiomeric recognition has focused on the interaction of chiral synthetic macrocycles
with chiral organic ammonium salts.6–10 Among the chiral macrocycles a number of enantiomerically
pure crown ethers containing pyridine6–8 pyrimidine9 and phenanthroline10 subcyclic units have been
studied. These studies have shown that hydrogen bonding, aromatic stacking (π–π interaction) and
steric repulsion are the three fundamental non-covalent intermolecular forces which are responsible for
enantiomeric recognition.6–10
Very recently, we described the preparation of the simplest phenazino-18-crown-6 ligand 1 and its
enantiomerically pure dimethyl-substituted analogue (R,R)-2 (Fig. 1) as the first two representatives of a
crown ether containing the phenazine unit.11
Figure 1. Structures of the phenazino-crown ethers and the ammonium salts
Optically active ligand (R,R)-2 has a tricyclic ring system which gives high rigidity to the portions
of the macro ring containing the stereogenic centers. Also, the extended π-system of the phenazine
ring provides a large area for π–π interactions with the chiral ammonium salts containing an aromatic
moiety, so a strong and tight association of the complexes can take place where the difference in
steric repulsion becomes more pronounced. Both features assist enantioselectivity.6–8,10 Our first studies
on enantiomeric recognition of α-(1-naphthyl)ethylammonium perchlorate (NEA) by enantiomerically
pure dimethylphenazino-18-crown-6 ligand (R,R)-2 in the solid state and in the gas phase (molecular
modeling) have shown high enantioselectivity of (R,R)-2 toward (S)-NEA over (R)-NEA in complex
formation.12 Our extensive studies on enantiomeric recognition of chiral organic ammonium salts by
chiral pyridino-18-crown-6 type ligands have also shown that the bulkiness of the substituents at the
stereogenic centers paralleled very well the enantioselectivity.6–8 Therefore, we designed and prepared
chiral phenazino-ligands (R,R)-3 and (S,S)-4 with bulky substituents. The intention of preparing chiral
crown ethers (R,R)-5–(S,S)-8 with side chains containing terminal double bonds was that these ligands
can be attached covalently to silica gel and the chiral stationary phase (CSP) so that, once obtained, they
can be used for enantioseparation of organic ammonium salts by chromatography as we reported in the
case of chiral pyridino-crown ethers.13–15
Besides the synthesis of chiral crown ethers shown in Fig. 1, we also report our preliminary circular
dichroism (CD) spectroscopic studies on enantiomeric recognition of most of them with the enantiomers
of NEA and α-phenylethylammonium perchlorate (PEA). These studies clearly show that the chiral
ligands containing the phenazine ring have high enantioselectivity for NEA and PEA.

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
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2. Results and discussion
Ligand (R,R)-2 was prepared by a modification of our procedure described in the literature,11 the main
difference being that the crude potassium tosylate complex of (R,R)-2 was not purified by recrystallization
as reported, but subjected directly to chromatography on alumina. This modification not only simplified
the purification and increased the yield of (R,R)-2, but also gave a general method for preparation of other
chiral phenazino-crown ligands (R,R)-3–(R,R)-7 (see Scheme 1).
Scheme 1. Preparation of chiral phenazino-crown ethers using phenazine-1,9-diol and chiral ditosylates
The cyclization reaction of phenazine-1,9-diol 9 and chiral ditosylate (S,S)-10 under the conditions
outlined in Scheme 1 resulted in complete inversion of configuration as proved indirectly earlier.11 Here
we present direct proof for the total inversion of configuration of both stereogenic centers during the
cyclization reactions shown in Scheme 1. When diols (S,S)-1616 and (S,S)-17 were reacted with 1,9-
dichlorophenazine 1917 in strong basic conditions (see Scheme 2), we measured for products (S,S)-2 and
(S,S)-7 which had the same magnitude, but opposite signs, of specific rotation as for products (R,R)-2
and (R,R)-7 formed from the ditosylates of (S,S)-16 and (S,S)-17 in the reaction shown in Scheme 1.
Scheme 2. Preparation of chiral phenazino-crown ethers using 1,9-dichlorophenazine and chiral diols
Since the reactions shown in Scheme 2 do not involve the stereogenic centers, retention of configu-
ration is assured. Since the rotations are of opposite signs, these results clearly demonstrate that the
cyclization outlined in Scheme 1 proceeds with complete inversion of configuration. Comparing the
yields of the two methods for obtaining chiral ligands (see Schemes 1 and 2) we can conclude that the
cyclization reactions shown in Scheme 1 give better yields when the chiral ditosylates contain no side
chain, and about the same yields when they do have a side chain.
Chiral ditosylates (S,S)-10–(S,S)-15 were prepared from the appropriate diols using tosyl chloride
(TsCl) in pyridine as both a base and a solvent (see Scheme 3). Tetraethylene glycols (S,S)-1616 and
(R,R)-2118 were prepared as reported. Tetraethylene glycol (S,S)-20 was prepared starting from (R)-(−)-
leucine [D-leucine] in the same way as reported for its enantiomer (R,R)-20 starting from (S)-(+)-leucine
[L-leucine].18
Diols (S,S)-17, (S,S)-18, (S,S)-22 and (S,S)-23 are novel compounds and their syntheses are shown in
Schemes 4 and 5. Diethyl allylmalonate 24 and diethyl diallylmalonate 25, respectively, were reduced
with LiAlH4 to produce diols 2619 and 27, respectively.

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Scheme 3. Preparation of chiral ditosylates from chiral diols
The latter compounds were transformed into ditosylates 28 and 29, respectively, using TsCl and
powdered KOH in THF, a well established method used in our laboratories11,13,14,18,20,21 for the pre-
paration of primary tosylates in excellent yields (see Scheme 4).
Scheme 4. Preparation of mono- and diallyl-substituted pentane-1,5-diols
Ditosylates 28 and 29 were treated with NaCN in DMSO to give dinitriles 30 and 31, respectively,
which were hydrolyzed under basic conditions followed by acidification with aqueous HCl to give
diacids 32 and 33, respectively. Reduction of diacids 32 and 33 with LiAlH4 in ether afforded substituted
pentane-1,5-diols 34 and 35, respectively. Diols 34 and 35 and tosylates (S)-38 and (S)-39 (see Scheme 5)
were the direct precursors of diols (S,S)-17, (S,S)-18, (S,S)-22 and (S,S)-23. Tosylate (S)-38 was prepared
from alcohol (S)-36 using TsCl and powdered KOH in THF as reported,21 except that since 34 and 35
are sensitive to any impurities, it was purified instead of using the crude product. Tosylate (S)-39 was
obtained in a similar manner from alcohol (S)-37. Diols 34 and 35 were treated first with KOt-Bu in
HMPA, then ditosylate (S)-38 or (S)-39 was added to perform a Williamson-type ether formation, and
Scheme 5. Preparation of mono- and diallyl-substituted chiral diols

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2779
finally the tetrahydropyranyl (THP) protecting groups were removed with strong acidic ion-exchange
resin in MeOH to give diols (S,S)-17, (S,S)-18, (S,S)-22 and (S,S)-23.
The UV/vis and CD spectral parameters of crown compounds containing the phenazine unit [1-(R,R)-
7] are summarized in Tables 1 and 2, respectively. The UV/vis spectrum of the parent achiral crown
molecule 1 shows three bands at 420, 362 and 268 nm. The broad long-wavelength band is composed of
two overlapping components between 430–390 and 390–310 nm.
Table 1
UV/vis spectral parameters of crown compounds [1–(R,R)-7] containing the phenazine unit, and of
aralkyl ammonium salts (NEA and PEA) in acetonitrile
The former component contributes to the n→π* transition while the latter one centered between
1
1
365–362 nm mainly belongs to the La transition.22 The La band is split but the fine structure is less
expressed than in the spectra of 9-anthroates which have three well-separated La UV bands.23b The
1
1Lb band is covered by the more intense La band system. The strongest band in the UV/vis spectrum
1
between 271 and 268 nm is assigned to the Bb band of the substituted phenazine chromophore.22 The
1
shoulder below 240 nm probably belongs to a transition which corresponds to the less intense 1Cb band
of anthracene derivatives having no center of symmetry. The Platt notations and polarization diagrams are
generally used for polyacene chromophores.23 In the case of phenazine the double replacement of N for
CH does not change the D2h symmetry of anthracene, the polarization directions of which are established
both experimentally and theoretically.23b
In the symmetrically substituted phenazino-crown host molecules the polarization directions of the
parent chromophore are not seriously affected. Therefore, the polarization diagram shown in Fig. 6 can be
used for determining the chirality of the coupled transition moments. Substituents in positions 3 and 13 or
the allyl linker group(s) attached at C8 of the carba-analogue of the parent crown do not result in marked
shifts of the position or intensity of the bands in the UV/vis spectrum of 1 (Table 1). The CD spectrum
of the most simple chiral phenazino-crown ether compound (R,R)-2 shows a negative n→π* band at
1
1
430 nm and a positive band at 358 nm due to the spectral contributions of the La and Lb transitions
(Table 2). The most interesting feature of the CD spectrum of (R,R)-2 (and other chiral derivatives of 1)
is the appearance of a negative and a positive band at about 280 and 265 nm, respectively (Figs. 2 and 3).
The crossover point at ∼270 nm corresponds to the λmax value of the 1Bb band in the UV/vis spectrum
(Table 1). The strongest positive band, accompanied by a short-wavelength shoulder, appears at 232 nm,
and the last measurable band at 202 nm in the spectrum of (R,R)-2 (Table 2) is again negative.
The same sign pattern is characteristic of the compounds (R,R)-3 and (S,S)-4 (having an additional
stereogenic center in the side chains). Compared to the bands measured in the case of (R,R)-2, the
intensity of the positive band at 268 nm in the spectra of (R,R)-3 and (S,S)-4 increases while that of the

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Table 2
CD data of crown compounds containing phenazine chromophores 1–(R,R)-7 and of aralkyl
ammonium salts (NEA and PEA), as well as CD spectra of their 1:1 complexes in acetonitrile

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2781
Figure 2. CD spectrum of crown ether host (R,R)-2, (R)- and (S)-PEA and the homo- and heterochiral complexes measured at a
host:guest molar ratio of 1:1 in acetonitrile
Figure 3. CD spectrum of crown ether host (R,R)-2, (R)- and (S)-NEA, and the 1:1 homo- and heterochiral complexes in
acetonitrile
negative band at 280 and 284 nm, respectively, decreases. (Note the negligible intensity of the negative
band in the spectrum of (S,S)-4.)
The replacement of O8 by carbon and the attachment of one or two allyl groups [crowns (R,R)-5
and (R,R)-6] do not have a significant influence upon the CD spectrum of the parent molecule (R,R)-2
(Table 2). The CD spectra are still dominated by a strong negative and a strong positive band in the 1Bb
region of the phenazine chromophore but the absolute intensity of the negative band decreases more than
that of the positive band. The allyl linker group in position C8 of (R,R)-7 has a stronger spectral effect

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
than in (R,R)-5 (Table 2 and Fig. 4). The UV and CD spectra of (R)- and (S)-forms of PEA and NEA
have been discussed earlier.24 CD spectra of the host–guest complexes were measured at a molar ratio
of 1:1 (Table 2). The stability constants (Ks) of complexes for similar systems are greater than 104 in
acetonitrile.7 Thus, due to their low concentrations, the contribution of the free host and guest molecules
to the CD spectrum of the complex can be neglected.24
Figure 4. Comparison of the CD spectra of the 1:1 homo- and heterochiral NEA complexes of crown ether hosts (R,R)-2,
(R,R)-5, and (R,R)-6, in acetonitrile
The enantiomeric recognition ability of chiral ligands (R,R)-2–(R,R)-7 towards aralkyl ammonium
salts NEA and PEA was evaluated: (i) by inspection of the spectra, i.e. comparing the spectral re-
sponses measured for the heterochiral [(R,R)-crown/(S)-guest or (S,S)-crown/(R)-guest] and homochiral
[(R,R)-crown/(R)-guest or (S,S)-crown/(S)-guest] complexes; (ii) by comparing the difference spectra,
∆∆ε=∆εcomplex–(∆εhost+∆εguest); and (iii) by comparing the CD spectra (or difference spectra) of the
1:1 complexes of the aralkyl ammonium salts to those of the achiral complexing agent butylammonium
perchlorate (BAP). CD spectra of BAP complexes also served as references for separating the chiral
effects of H-bonding from those of aromatic interactions. Spectral additivity, i.e. a difference spectrum
close to zero over the whole spectral range, was regarded as the sign of no or weak attractive interactions
and therefore the lack of complex formation. In the majority of cases heterochiral or homochiral prefe-
rence was clearly reflected by the shape of the CD spectra (or difference spectra) of the diastereomeric
complexes (Fig. 3). Some of the complexes, however, showed different chiroptical behavior above and
below ∼300 nm. The same or a similar spectral responses above ∼300 nm but significant changes in
the 1Bb or 1Cb spectral regions were considered as an indication of strong π–π interaction between the
host and guest molecules without a significant effect of H-bonding on the chromophoric system of the
crown ether. Contrary to this, a whole range similarity of the CD spectra of the BAP complex and the
complex of one of the enantiomeric aralkyl ammonium salts clearly indicated the dominance of H-bond
formation.
CD data on the enantiomeric recognition ability of chiral ligands (R,R)-2–(R,R)-7 towards PEA showed
an almost general heterochiral preference in the whole spectral range. Except for the crowded crown

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2783
host (R,R)-6 having two allyl side chains, analogues (R,R)-5 and (R,R)-7 with one linker showed a
discriminating power comparable to that of the parent host molecules (R,R)-2 and (R,R)-3.
Phenazino-crown ether hosts formed stable complexes with both enantiomers of NEA. The CD spectra
of the 1:1 complexes showed bands with exceedingly high amplitude (Table 2). The most intense positive
band at 225 nm (∆ε=179) appeared in the spectrum of the (R,R)-2/(S)-NEA complex (Fig. 3). Based on
the band positions, signs and intensities, the CD spectra, in general, are marked by a short-wavelength
asymmetric exciton couplet.23b It is only the CD spectra of the NEA complexes of crown (R,R)-6
featuring two allyl linker groups, which showed bands with significantly lower intensity (Table 2, Fig. 4).
The short-wavelength (<310 nm) region of the CD spectra and the corresponding difference spectra
(not shown) clearly showed heterochiral preference of the host molecules. Crown (S,S)-4, having (S)-
sec-butyl groups attached to carbons 3 and 13, showed, as expected, couplets of opposite signs with less
intense bands (Fig. 5).
Figure 5. Comparison of the CD spectra of the 1:1 homo- and heterochiral NEA complexes of crown ether hosts (R,R)-2,
(R,R)-3, and (S,S)-4, in acetonitrile
In the region above ∼310 nm, the CD spectra featuring a negative longer-wavelength and a positive
shorter-wavelength band also reflected heterochiral preference of the host molecules (Table 2). Only
the band centered near 360 nm showed comparable intensity or higher amplitude for the homochiral
complex.
The sign of the exciton couplet allowed determination of the relative orientation of the phenazine
and naphthalene chromophores in the complexes. All (R,R)-crown/(S)-NEA exciton spectra showed the
following sign and intensity pattern of bands below ∼310 nm: +Iw, −Is, sh, +Ivs, −Im,s. Considering the
λ
max values of bands in the UV/vis spectrum, the above sign pattern of extremely and moderately intense
bands can be explained by multiple coupling of the 1Cb and 1Bb transitions of the phanazine and 1Bb and
1La transitions of the naphthalene chromophores. Multiple coupling is well known in the literature of CD
spectroscopy25 but has not yet been observed in the field of aromatic crown complexes. The chiroptical
behavior of crown ether complexes resembles that of 4-substituted [2.2]paracyclophanes which show
complex CD spectra comprising three exciton couplets in the 1Lb, 1La and 1Bb spectral regions.26 Fig. 6a

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
shows the transition dipole directions of the phanazine and naphthalene chromophores.22 The short-
wavelength couplet with bands at ∼210 and ∼225 nm is positive for all heterochiral NEA complexes
of (R,R)-hosts. On the basis of the λmax values of the naphthalene and phenazine transitions in the UV
1
1
spectrum, the intense positive couplet reflects the interaction of the naphthalene Bb and phenazine Cb
transitions.
The exciton chirality rule23 predicts a negative torsion or projection angle between the long axes of the
chromophores in the heterochiral complex (Fig. 6b). (The 1Bb electric transition moment vectors roughly
parallel the long axes of the rings.22) This corresponds to a positive sign of the dominant short-wavelength
couplet in the spectra of the heterochiral complexes. The homochiral complex25 also results in a strong
dominant couplet but with opposite (negative) sign and decreased band intensities. This suggests a
positive projection angle between the long axes (Fig. 6c). This orientation also allows an extended π–π
interaction between the electron-rich naphthalene ring and the electron-poor parts of the phenazine ring.
However, the repulsion between the hydrogens attached in positions 2 and 3 at the naphthalene ring and
the upwardly oriented substituent in position 13 of the crown ether macro ring (Fig. 6d) loosens the
complex giving rise to less intense bands in the CD spectrum. In the heterochiral case the larger distance
between the side chain at C3 of the crown and the closest atoms of the naphthalene ring (Fig. 6b) are
favorable for both H-bonding and π–π interaction explaining the extremely intense exciton couplets
in the CD spectrum. The suggested geometry of the heterochiral (Fig. 6b) and homochiral complexes
(Fig. 6d) is strongly supported by a comparison of the CD spectra of the NEA complexes of crowns
(R,R)-2, (R,R)-3 and (S,S)-4 (Fig. 5).
Figure 6. Polarization directions (a, c) and relative orientation of the aromatic ring systems (b, d) in the NEA complexes of
(R,R)-phenazino-crown ether hosts
The band amplitudes decrease more in the homochiral than in the heterochiral case upon the increase
of the bulkiness of the crown substituents at C3 and C13. The opposite, (S,S)-configuration of crown
(S,S)-4, leads to negative instead of positive couplets in the spectrum of the heterochiral complex. The
band intensities in the CD spectrum of the homochiral (S,S)-4/(S)-NEA complex are at the borderline of
the requirements of exciton chirality (Table 2).
The high amplitude of the band near ∼270 nm [∆ε=−73.7 for the (R,R)-2/(S)-NEA complex] and the
long-wavelength shoulder of the strongest band of the complexes suggest exciton interaction between

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2785
1
1
1
the naphthalene La and phenazine Bb transitions and/or Bb transitions of both chromophores. Theo-
retical calculations to analyze the long-wavelength region of the spectra are in progress. Recent X-ray
crystallographic data12 on the heterochiral and homochiral complexes of (R,R)-2 with (S)- and (R)-NEA
show negative and positive projection angles between the long axes in the heterochiral and homochiral
complex, respectively. This is in agreement with the positive sign of the short-wavelength couplet due to
1
1
exciton interaction between the naphthalene Bb and phenazine Cb transitions in the heterochiral NEA
complexes (Fig. 6). Notably, the positive sign of the possible 1La/1Bb and the negative sign of the 1Bb/1Bb
exciton couplets also predict a geometry which agrees with the X-ray crystallography-based structure of
the heterochiral complex (Fig. 6b).12
Attachment of one allyl linker group at C8 of the carba-analogues of (R,R)-5 and (R,R)-7 also results
in couplets (positive–positive in the heterochiral and negative–negative in the homochiral cases) with
decreased band intensities when complexing with the NEA enantiomers. Notably, the longer-wavelength
couplet is practically not present in the spectrum of the NEA complexes of crown (R,R)-7, while the
low band intensities and other spectral features suggest only negligible exciton interaction and chiral
discriminating power of crown (R,R)-6 with two allyl groups at C8 (Table 2).
Results of the CD studies discussed above clearly show that chiral crown compounds (R,R)-2–(R,R)-
7 containing the phenazine unit are superior to pyridino-18-crown-6 ligands24 as chiral selectors. CD
spectroscopy revealed an almost general heterochiral preference of ligands (R,R)-2–(R,R)-7 for NEA and
PEA.
More importantly, the presence of one allyl linker at C8 of the carba-analogues (R,R)-5 and (R,R)-7
does not result in a significant decrease of the discriminating power.
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
enantiomers of menthol.
1H (500 MHz) and 13C (125 MHz) NMR spectra were taken on a Bruker DRX-500 Avance spectro-
meter and 1H (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 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 well established methods.27 Evaporations were carried out under reduced pressure
unless otherwise stated.
CD spectra were recorded on a Jobin–Yvon Mark VI dichrograph (calibrated with epiandrosterone) at
room temperature using a 0.02 cm cell for measurements between 195 and 240 nm and 0.1, 0.2 or 0.5 cm
cells above 240 nm. Acetonitrile (Merck, for chromatography) was used as solvent and the concentration
ranged from 0.5 to 5 mmol dm−3, depending on the absorption.

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3.1. (3R,13R)-(−)-3,13-Dimethyl-2,5,8,11,14-pentaoxa-20,26-diazatetracyclo[13.9.3.019,27 .021,25]-
heptacosa-1(25),15,17,19,21,23,26-heptaene (R,R)-2
A mixture of phenazine-1,9-diol 911 (424 mg, 2 mmol), ditosylate (S,S)-10 (1.06 g, 2 mmol), finely
powdered anhydrous K2CO3 (2.76 g, 20 mmol) and DMF (50 mL) was stirred under Ar at room
temperature for 10 min then at 50°C for 5 days. The solvent was removed at 50°C and the residue
was taken up in a mixture of ice-water (30 mL) and EtOAc (60 mL). The aqueous phase was extracted
with EtOAc (3×30 mL). The combined organic phase was dried over MgSO4, filtered, and the solvent
evaporated. Chromatography on alumina using 2% EtOH in toluene as an eluent, then recrystallization
from EtOH, gave (R,R)-2 (462 mg, 58%) as yellow crystals identical in every aspect to that reported.11
3.2. (3S,13S)-(+)-3,13-Dimethyl-2,5,8,11,14-pentaoxa-20,26-diazatetracyclo[13.9.3.019,27 .021,25]-
heptacosa-1(25),15,17,19,21,23,26-heptaene (S,S)-2
A mixture of NaH (112 mg, 2.8 mmol, 60% dispersion in mineral oil), (2S,12S)-(+)-4,7,10-
trioxatridecane-2,12-diol (S,S)-1616 (222 mg, 1 mmol) and diglyme (12 mL) was stirred under Ar at
room temperature for 10 min then at 90°C for 1 h. The reaction mixture was cooled to room temperature
and 1,9-dichlorophenazine 1917 (249 mg, 1 mmol) was added, then it was stirred at 90°C for 3 days. The
solvent was evaporated (0.2 mmHg) and the residue was taken up in ice-water (28 mL) and EtOAc (50
mL). The aqueous phase was extracted with EtOAc (3×25 mL). The combined organic phase was shaken
with distilled water (50 mL), dried over MgSO4, filtered and the solvent evaporated. Chromatography on
alumina using 2% EtOH in toluene as an eluent, then recrystallization from EtOH gave (S,S)-2 (88 mg,
22%) as yellow crystals. [α]25=+121.4 (c 0.210, CH2Cl2); lit.11 [α]25=−121.5 (c 0.521, CH2Cl2) for
D
D
the other enantiomer (R,R)-2. All other physical and spectral data were identical to those reported11 for
(R,R)-2.
3.3. (3R,13R)-(−)-3,13-Diisobutyl-2,5,8,11,14-pentaoxa-20,26-diazatetracyclo[13.9.3.019,27 .021,25]-
heptacosa-1(25),15,17,19,21,23,26-heptaene (R,R)-3
Macrocycle (R,R)-3 was prepared as described above for macrocycle (R,R)-2 starting from phenazine-
1,9-diol 9 (424 mg, 2 mmol) and ditosylate (S,S)-11 (1.23 g, 2 mmol). The reaction was completed at
50°C in 10 days. Chromatography on alumina using 1% EtOH in toluene as an eluent, then recrystalli-
zation from EtOH gave (R,R)-3 (492 mg, 51%) as yellow crystals. Mp 83°C (EtOH); Rf=0.31 (alumina
TLC, 2% EtOH in toluene); [α]25=−36.4 (c 1.04, CH2Cl2); IR (KBr) 2960, 2920, 2870, 1610, 1560,
D
1480, 1410, 1330, 1260, 1100, 930, 900, 820, 750 cm−1; 1H NMR (500 MHz) δ 0.93 (d, J=6 Hz, 6H),
0.99 (d, J=6 Hz, 6H), 1.69–1.74 (m, 2H), 1.80–1.91 (m, 4H), 3.67–3.74 (m, 6H), 3.87–3.96 (m, 4H), 4.23
(d, J=2 Hz, 1H), 4.26 (d, J=2 Hz, 1H), 5.18–5.23 (m, 2H), 7.15 (d, J=8 Hz, 2H), 7.72 (t, J=8 Hz, 2H),
7.80 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 23.04, 23.31, 25.13, 39.67, 71.63, 71.72, 73.19, 78.69,
112.03, 121.79, 131.07, 136.78, 144.46, 154.62; HRMS (EI) calcd for C28H38N2O5: 482.2781; found:
482.2804; anal. calcd for C28H38N2O5: C, 69.67; H, 7.94; N, 5.81; found: C, 69.65; H, 7.94; N, 5.68.
3.4. (3S,13S)-(−)-3.13-Di-[(S)-sec-butyl]-2,5,8,11,14-pentaoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (S,S)-4
Macrocycle (S,S)-4 was prepared as described above for macrocycle (R,R)-2 starting from phenazine-
1,9-diol 9 (424 mg, 2 mmol) and ditosylate (R,R)-12 (1.23 g, 2 mmol). The reaction was completed at

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2787
50°C in 15 days. Chromatography on alumina using 1% EtOH in toluene as an eluent, then recrystalli-
zation from EtOH gave (S,S)-4 (502 mg, 52%) as yellow crystals. Mp 68°C (EtOH); Rf=0.36 (alumina
TLC, 2% EtOH in toluene); [α]25=−6.6 (c 1.32, CH2Cl2); IR (KBr) 2970, 2930, 2900, 2870, 1610, 1560,
D
1490, 1460, 1410, 1320, 1280, 1110, 1040, 910, 830, 760 cm−1; 1H NMR (500 MHz) δ 0.90 (t, J=7 Hz,
6H), 1.02 (d, J=7 Hz, 6H), 1.26–1.32 (m, 2H), 1.64–1.72 (m, 2H), 2.08–2.13 (m, 2H), 3.66–3.79 (m, 8H),
4.13–4.16 (m, 2H), 4.21–4.23 (m, 2H), 5.25–5.28 (m, 2H), 7.20 (d, J=8 Hz, 2H), 7.71 (t, J=8 Hz, 2H),
7.81 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 12.02, 14.79, 26.08, 36.12, 71.40, 71.59, 72.31, 83.88,
113.56, 122.03, 131.35, 136.86, 144.53, 154.96; HRMS (EI) calcd for C28H38N2O5: 482.2781; found:
482.2790; anal. calcd for C28H38N2O5: C, 69.67; H, 7.94; N, 5.81; found: C, 69.53; H, 7.97; N, 5.53.
3.5. (3R,13R)-(−)-3,13-Dimethyl-8-(2-propenyl)-2,5,11,14-tetraoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (R,R)-5
Macrocycle (R,R)-5 was prepared as described above for macrocycle (R,R)-2 starting from phenazine-
1,9-diol 9 (424 mg, 2 mmol) and ditosylate (S,S)-13 (1.14 g, 2 mmol). The reaction was completed at
50°C in 6 days. Chromatography on alumina using 1% EtOH in toluene as an eluent, then recrystalliza-
tion from EtOH gave (R,R)-5 (320 mg, 41%) as yellow crystals. Mp 102°C (EtOH); Rf=0.38 (alumina
TLC, 2% EtOH in toluene); [α]25=−86.4 (c 1.04, CH2Cl2); IR (KBr) 3080, 3070, 3060, 2970, 2930,
D
2910, 2850, 1640, 1590, 1560, 1480, 1450, 1410, 1330, 1310, 1290, 1260, 1150, 1110, 1050, 900, 820,
1
740 cm−1; H NMR (500 MHz) δ 1.47 (d, J=7 Hz, 3H), 1.49 (d, J=7 Hz, 3H), 1.57–1.70 (m, 4H),
1.85–1.90 (m, 1H), 2.04 (t, J=7 Hz, 2H), 3.63–3.99 (m, 8H), 4.93–4.97 (m, 2H), 5.12–5.18 (m, 2H),
5.66–5.75 (m, 1H), 7.10 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.72 (t, J=8 Hz, 2H), 7.79 (d, J=8 Hz,
1H), 7.80 (d, J=8 Hz, 1H); 13C NMR (125 MHz) δ 15.70, 16.02, 31.33, 33.36, 33.83, 39.77, 69.63, 70.15,
73.62, 73.73, 75.19, 75.54, 110.72, 111.11, 116.06, 121.41, 121.55, 130.83, 130.86, 136.63, 136.68,
137.14, 144.24, 144.29, 153.91, 153.96; HRMS (EI) calcd for C26H32N2O4: 436.2362; found: 436.2363;
anal. calcd for C26H32N2O4: C, 71.52; H, 7.39; N, 6.42; found: C, 71.31; H, 7.51; N, 6.40.
3.6. (3R,13R)-(−)-3,13-Dimethyl-8,8-bis(2-propenyl)-2,5,11,14-tetraoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (R,R)-6
Macrocycle (R,R)-6 was prepared as described above for macrocycle (R,R)-2 starting from phenazine-
1,9-diol 9 (212 mg, 1 mmol) and ditosylate (S,S)-14 (609 mg, 1 mmol). The reaction was completed at
50°C in 10 days. Chromatography on alumina using 2% EtOH in toluene as an eluent, then recrystalli-
zation from EtOH gave (R,R)-6 (95 mg, 20%) as yellow crystals. Mp 63°C (EtOH); Rf=0.44 (alumina
TLC, 2% EtOH in toluene); [α]25=−64.2 (c 1.63, CH2Cl2); IR (KBr) 3080, 2970, 2930, 2840, 1640,
D
1
1600, 1560, 1540, 1480, 1450, 1410, 1330, 1310, 1270, 1150, 1120, 1080, 900, 830, 740 cm−1; H
NMR (500 MHz) δ 1.51 (d, J=6 Hz, 6H), 1.61–1.67 (m, 4H), 2.01 (d, J=7 Hz, 4H), 3.67–3.89 (m, 8H),
4.97–5.03 (m, 4H), 5.22–5.27 (m, 2H), 5.75–5.83 (m, 2H), 7.12 (d, J=8 Hz, 2H), 7.72 (t, J=8 Hz, 2H),
7.81 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 16.64, 36.66, 38.10, 42.30, 68.73, 74.60, 76.00, 111.79,
117.99, 121.96, 131.35, 135.01, 136.97, 144.60, 154.59; HRMS (EI) calcd for C29H36N2O4: 476.2675;
found: 476.2682; anal. calcd for C29H36N2O4: C, 73.07; H, 7.62; N, 5.88; found: C, 72.90; H, 7.84; N,
5.81.

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
3.7. (3R,13R)-(−)-3,13-Diisobutyl-8-(2-propenyl)-2,5,11,14-tetraoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (R,R)-7
Macrocycle (R,R)-7 was prepared as described above for macrocycle (R,R)-2 starting from phenazine-
1,9-diol 9 (212 mg, 1 mmol) and ditosylate (S,S)-15 (653 mg, 1 mmol). The reaction was completed at
50°C in 10 days. The crude product was purified by chromatography first on alumina using 0.5% EtOH in
toluene, then on silica gel using 4% EtOH in toluene as eluent to give (R,R)-7 (52 mg, 10%) as a yellow
oil. Rf=0.52 (alumina TLC, 2% EtOH in toluene); [α]25=−27.3 (c 0.460, CH2Cl2); IR (KBr) 3080, 2960,
D
2920, 2870, 1640, 1580, 1490, 1480, 1400, 1320, 1280, 1100, 830, 770, 680 cm−1; 1H NMR (500 MHz)
δ 0.98 (d, J=8 Hz, 3H), 1.01 (d, J=8 Hz, 3H), 1.03 (d, J=8 Hz, 3H), 1.04 (d, J=8 Hz, 3H), 1.42–1.47
(m, 2H), 1.49–1.55 (m, 4H), 1.66–1.71 (m, 2H), 1.84–1.90 (m, 2H), 1.91–1.96 (m, 1H), 2.15–2.20 (m,
2H), 3.47–3.75 (m, 6H), 3.92–4.02 (m, 2H), 4.84–4.90 (m, 2H), 5.18–5.23 (m, 1H), 5.53–5.59 (m, 1H),
5.59–5.64 (m, 1H), 7.17 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.72 (t, J=8 Hz, 1H), 7.73 (t, J=8 Hz,
1H), 7.82 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz, 1H); 13C NMR (125 MHz) δ 23.09, 23.12, 23.19, 23.26,
25.03, 25.10, 31.56, 33.14, 33.79, 39.91, 40.12, 40.48, 69.85, 69.88, 72.49, 72.79, 78.12, 78.20, 111.76,
113.15, 116.08, 121.65, 122.06, 131.01, 131.03, 136.80, 137.13, 137.24, 144.35, 144.41, 154.60, 154.92;
HRMS (EI) calcd for C32H44N2O4: 520.3301; found: 520.3287; anal. calcd for C32H44N2O4: C, 73.80;
H, 8.52; N, 5.38; found: C, 73.65; H, 8.41; N, 5.22.
3.8. (3S,13S)-(+)-3,13-Diisobutyl-8-(2-propenyl)-2,5,11,14-tetraoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (S,S)-7
Macrocycle (S,S)-7 was prepared as described above for macrocycle (S,S)-2 starting from diol (S,S)-17
(172 mg, 0.5 mmol) and 1,9-dichlorophenazine 19 (125 mg, 0.5 mmol). The reaction was completed at
90°C in 6 days. The crude product was purified by chromatography first on alumina using 0.5% EtOH in
toluene, then on silica gel using 4% EtOH in toluene as eluent to give (S,S)-7 (42 mg, 16%) as a yellow oil.
[α]25=+27.35 (c 0.200, CH2Cl2). All other physical and spectral data were identical to (R,R)-7 described
D
above.
3.9. (3R,13R)-(+)-3,13-Diisobutyl-8,8-bis(2-propenyl)-2,5,11,14-tetraoxa-20,26-diazatetracyclo-
[13.9.3.019,27.021,25]heptacosa-1(25),15,17,19,21,23,26-heptaene (S,S)-8
Macrocycle (S,S)-8 was prepared as described above for macrocycle (S,S)-2 starting from diol (S,S)-18
(192 mg, 0.5 mmol) and 1,9-dichlorophenazine 19 (125 mg, 0.5 mmol). The reaction was completed at
90°C in 10 days. The crude product was purified by chromatography first on alumina using 0.3% EtOH
in toluene, then on silica gel using 2.5% EtOH in toluene as eluent to give (R,R)-8 (39 mg, 14%) as a
yellow oil. Rf=0.61 (alumina TLC, 2% EtOH in toluene); [α]25=+22.35 (c 0.680, CH2Cl2); IR (KBr)
D
3080, 2970, 2940, 2880, 1640, 1620, 1600, 1560, 1470, 1460, 1370, 1320, 1260, 1110, 830, 750, 660
cm−1; 1H NMR (500 MHz) δ 1.01 (d, J=6 Hz, 6H), 1.02 (d, J=6 Hz, 6H), 1.45–1.51 (m, 4H), 1.65–1.69
(m, 2H), 1.89 (d, J=7 Hz, 4H), 1.91–1.99 (m, 4H), 3.51–3.56 (m, 2H), 3.62–3.71 (m, 4H), 4.00–4.03
(m, 2H), 4.91–4.98 (m, 4H), 5.33–5.38 (m, 2H), 5.66–5.74 (m, 2H), 7.18 (d, J=8 Hz, 2H), 7.72 (t, J=8
Hz, 2H), 7.82 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 23.13, 23.35, 25.08, 36.06, 37.55, 40.83, 41.91,
68.20, 73.01, 78.24, 112.82, 117.75, 122.02, 131.09, 134.56, 136.90, 144.43, 154.95; HRMS (EI) calcd
for C35H48N2O4: 560.3614; found: 560.3618; anal. calcd for C35H48N2O4: C, 74.95; H, 8.63; N, 5.00;
found: C, 75.11; H, 8.54; N, 5.16.

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2789
3.10. (2S,12S)-(−)-4,7,10-Trioxatridecane-2,12-diol di-p-tosylate (S,S)-10
To a stirred solution of (2S,12S)-(+)-4,7,10-trioxatridecane-2,12-diol (S,S)-1616 (2.22 g, 10 mmol) in
pyridine (10 mL) at 0°C and under Ar was added tosyl chloride (4.19 g, 22 mmol) dissolved in pyridine
(20 mL). The reaction mixture was stirred at 0°C for 10 min, and at room temperature for 1 day, then
it was poured into ice-water (150 mL). This stirred mixture was made weakly acidic (pH=3) with 37%
aqueous HCl at 0°C then extracted with ether (1×400, 3×200 mL). The combined organic phase was
shaken with 3% aqueous HCl (1×150 mL), distilled water (1×500 mL), and saturated brine (2×300
mL), then dried over MgSO4 and filtered, and the solvent evaporated. The crude product was purified by
chromatography on silica gel using 9% EtOAc in toluene as an eluent to give (S,S)-10 (4.72 g, 89%) as a
colorless oil identical in every aspect to that prepared by the literature procedure.11
3.11. (4S,14S)-(−)-2,16-Dimethyl-6,9,12-trioxaheptadecane-4,14-diol di-p-tosylate (S,S)-11
Ditosylate (S,S)-11 was prepared as described above for ditosylate (S,S)-10 using (4S,14S)-(−)-
2,16-dimethyl-6,9,12-trioxaheptadecane-4,14-diol [(S,S)-20, see above in results and discussion] (3.06
g, 10 mmol). This time the reaction was completed in 2 days. The crude product was purified by
chromatography on silica gel using 9% EtOAc in toluene as an eluent to give (S,S)-11 (5.72 g, 93%)
as a colorless oil. Rf=0.48 (silica gel TLC, 20% EtOAc in toluene); [α]25=−2.2 (c 4.72, CH2Cl2); IR
D
(film) 3080, 3050, 3030, 2970, 2930, 2910, 2870, 1590, 1490, 1470, 1370, 1190, 1180, 1110, 1090, 910,
810, 770, 660 cm−1; 1H NMR (500 MHz) δ 0.79 (d, J=6 Hz, 6H), 0.86 (d, J=6 Hz, 6H), 1.40–1.45 (m,
2H), 1.55–1.63 (m, 4H), 2.45 (s, 6H), 3.48–3.59 (m, 12H), 4.69–4.73 (m, 2H), 7.33 (d, J=8 Hz, 4H), 7.81
(d, J=8 Hz, 4H); 13C NMR (125 MHz) δ 21.75, 21.99, 23.15, 24.22, 40.64, 70.59, 70.96, 72.68, 80.62,
127.97, 129.76, 134.69, 144.58.
3.12. (3S,4R,14R,15S)-(−)-3,15-Dimethyl-6,9,12-trioxaheptadecane-4,14-diol di-p-tosylate (R,R)-12
Ditosylate (R,R)-12 was prepared as described above for ditosylate (S,S)-10 using (3S,4R,14R,15S)-
(−)-3,15-dimethyl-6,9,12-trioxaheptadecane-4,14-diol [(R,R)-21]16 (3.06 g, 10 mmol). This time the
reaction was completed in 2 days. The crude product was purified by chromatography on silica gel using
9% EtOAc in toluene as an eluent to give (R,R)-12 (5.41 g, 88%) as a colorless oil. Rf=0.53 (silica gel
TLC, 20% EtOAc in toluene); [α]25=−13.4 (c 4.79, CH2Cl2); IR (film) 3080, 3050, 3030, 2980, 2950,
D
2910, 2890, 1600, 1500, 1480, 1380, 1200, 1190, 1120, 1100, 910, 810, 790, 680 cm−1; 1H NMR (500
MHz) δ 0.82 (t, J=7 Hz, 6H), 0.85 (d, J=7 Hz, 6H), 1.06–1.12 (m, 2H), 1.34–1.40 (m, 2H), 1.72–1.76 (m,
2H), 2.43 (s, 6H), 3.43–3.60 (m, 12H), 4.61–4.64 (m, 2H), 7.30 (d, J=8 Hz, 4H), 7.79 (d, J=8 Hz, 4H);
13C NMR (125 MHz) δ 11.57, 13.86, 21.62, 25.31, 36.11, 70.40, 70.43, 70.68, 84.80, 127.83, 129.55,
134.73, 144.30.
3.13. (2S,12S)-(−)-7-(2-Propenyl)-4,10-dioxatridecane-2,12-diol di-p-tosylate (S,S)-13
Ditosylate (S,S)-13 was prepared as described above for ditosylate (S,S)-10 using diol (S,S)-22 (2.60 g,
10 mmol). The crude product was purified by chromatography on silica gel using 9% EtOAc in toluene
as an eluent to give (S,S)-13 (5.40 g, 95%) as a colorless oil. Rf=0.60 (silica gel TLC, 20% EtOAc
in toluene); [α]25=−8.5 (c 1.04, CH2Cl2); IR (film) 3080, 3050, 3030, 2980, 2920, 2860, 1640, 1590,
D
1480, 1450, 1350, 1190, 1180, 1110, 1090, 910, 900, 800, 760, 660 cm−1; 1H NMR (500 MHz) δ 1.25
(d, J=6 Hz, 6H), 1.36–1.46 (m, 4H), 1.51–1.56 (m, 1H), 1.97 (t, J=7 Hz, 2H), 2.42 (s, 6H), 3.32–3.45

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
(m, 8H), 4.64–4.69 (m, 2H), 4.97–5.00 (m, 2H), 5.64–5.72 (m, 1H), 7.31 (d, J=8 Hz, 4H), 7.78 (d, J=8
Hz, 4H); 13C NMR (125 MHz) δ 17.69, 21.63, 31.49, 33.18, 38.08, 69.54, 72.98, 78.13, 116.43, 127.81,
129.69, 134.39, 136.48, 144.47.
3.14. (2S,12S)-(−)-7,7-Bis(2-propenyl)-4,10-dioxatridecane-2,12-diol di-p-tosylate (S,S)-14
Ditosylate (S,S)-14 was prepared as described above for ditosylate (S,S)-10 using diol (S,S)-23 (3 g, 10
mmol). The crude product was purified by chromatography on silica gel using 6% EtOAc in toluene as an
eluent to give (S,S)-14 (5.72 g, 94%) as a colorless oil. Rf=0.69 (silica gel TLC, 20% EtOAc in toluene);
[α]25=−8.5 (c 1.258, CH2Cl2); IR (film) 3080, 3050, 3030, 2970, 2930, 2910, 2870, 1640, 1600, 1500,
D
1
1460, 1380, 1200, 1190, 1110, 1090, 1000, 930, 820, 780, 680 cm−1; H NMR (500 MHz) δ 1.25 (d,
J=6 Hz, 6H), 1.39 (t, J=7 Hz, 4H), 1.93 (d, J=7 Hz, 4H), 2.43 (s, 6H), 3.35–3.43 (m, 8H), 4.64–4.70 (m,
2H), 5.00–5.07 (m, 4H), 5.70–5.78 (m, 2H), 7.31 (d, J=8 Hz, 4H), 7.79 (d, J=8 Hz, 4H); 13C NMR (125
MHz) δ 18.10, 22.04, 36.29, 37.33, 42.09, 67.97, 73.50, 78.52, 118.23, 128.22, 130.10, 134.63, 134.78,
144.88.
3.15. (4S,14S)-(−)-2,16-Dimethyl-9-(2-propenyl)-6,12-dioxaheptadecane-4,14-diol di-p-tosylate
(S,S)-15
Ditosylate (S,S)-15 was prepared as described above for ditosylate (S,S)-10 using diol (S,S)-17 (3.06
g, 10 mmol). This time the reaction was completed in 2 days. The crude product was purified by
chromatography on silica gel using 5% EtOAc in toluene as an eluent to give (S,S)-15 (6.20 g, 95%)
as a colorless oil. Rf=0.75 (silica gel TLC, 20% EtOAc in toluene); [α]25=−15.2 (c 1.279, CH2Cl2);
D
IR (film) 3080, 2960, 2920, 2870, 1640, 1590, 1500, 1470, 1370, 1200, 1180, 1120, 1100, 910, 810,
780, 680 cm−1; 1H NMR (500 MHz) δ 0.78 (d, J=6 Hz, 6H), 0.85 (d, J=6 Hz, 6H), 1.38–1.46 (m, 6H),
1.54–1.62 (m, 5H), 1.99 (t, J=7 Hz, 2H), 2.44 (s, 6H), 3.31–3.46 (m, 8H), 4.65–4.69 (m, 2H), 4.98–5.03
(m, 2H), 5.66–5.75 (m, 1H), 7.32 (d, J=8 Hz, 4H), 7.80 (d, J=8 Hz, 4H); 13C NMR (125 MHz) δ 21.80,
22.03, 23.18, 24.26, 31.71, 33.30, 38.18, 40.75, 69.74, 72.16, 80.64, 116.60, 127.98, 129.79, 134.70,
136.66, 144.59.
3.16. (4S,14S)-(+)-2,16-Dimethyl-9-(2-propenyl)-6,12-dioxaheptadecane-4,14-diol (S,S)-17
To a well-stirred mixture of KOt-Bu (5.38 g, 0.048 mol) and HMPA (40 mL) was added in an ice-water
bath and under Ar 3-(2-propenyl)-pentan-1,5-diol (34) (1.73 g, 0.012 mol). The reaction mixture was
stirred in the ice-water bath for 5 min then (S)-(−)-4-methyl-2[(tetrahydro-2H-pyran-2-yl)oxy]-pentan-
1-ol p-tosylate [(S)-39, see later] (11.11 g, 0.031 mol) was added and stirring was continued in the ice-
water bath for 20 min and at room temperature for 1 day. The resulting mixture was taken up in ice-water
(150 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 was dissolved in MeOH (100 mL) and Amberlite® IR-120 ion-
exchange resin (H+ form) (1 g) was added to this solution. After stirring the mixture at room temperature
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 (S,S)-17 (2.56 g, 62%)
as a colorless oil. Rf=0.58 (silica gel TLC, 14% acetone in CH2Cl2); [α]25=+1.9 (c 2.040, CH2Cl2); IR
D

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2791
1
(film) 3600–3100 (broad), 3080, 2960, 2920, 2870, 1640, 1480, 1380, 1100, 1000, 910, 850 cm−1; H
NMR (500 MHz) δ 0.89 (d, J=7 Hz, 6H), 0.91 (d, J=7 Hz, 6H), 1.07–1.15 (m, 2H), 1.35–1.42 (m, 2H),
1.56–1.61 (m, 4H), 1.74–1.81 (m, 3H), 2.05 (t, J=7 Hz, 2H), 3.07 (broad s, 2H), 3.16–3.56 (m, 8H),
3.79–3.85 (m, 2H), 4.97–5.02 (m, 2H), 5.70–5.78 (m, 1H); 13C NMR (125 MHz) δ 22.22, 22.26, 23.55,
23.56, 24.56, 24.59, 31.60, 33.19, 33.32, 38.74, 42.02, 42.11, 68.46, 68.50, 69.25, 69.43, 75.96, 76.19,
116.59, 136.76.
3.17. (4S,14S)-(+)-2,16-Dimethyl-9,9-bis(2-propenyl)-6,12-dioxaheptadecane-4,14-diol (S,S)-18
Diol (S,S)-18 was prepared as described above for diol (S,S)-17 starting from diol 35 (2.21 g, 12 mmol)
and tosylate (S)-39 (11.11 g, 31 mmol). The crude product was purified by chromatography on silica gel
using 5% acetone in CH2Cl2 as an eluent to give (S,S)-18 (1.87 g, 60%) as a colorless oil. Rf=0.68 (silica
gel TLC, 14% acetone in CH2Cl2); [α]25=+0.15 (c 4.660, CH2Cl2); IR (film) 3600–3100 (broad), 3080,
D
1
2960, 2920, 2870, 1640, 1480, 1380, 1100, 1000, 910, 860 cm−1; H NMR (500 MHz) δ 0.91 (d, J=7
Hz, 6H), 0.92 (d, J=7 Hz, 6H), 1.10–1.15 (m, 2H), 1.36–1.42 (m, 2H), 1.61 (t, J=7 Hz, 4H), 1.77–1.81
(m, 2H), 1.96–2.03 (m, 4H), 3.01 (broad s, 2H), 3.19–3.55 (m, 8H), 3.82–3.85 (m, 2H), 5.03–5.09 (m,
4H), 5.75–5.83 (m, 2H); 13C NMR (125 MHz) δ 22.31, 23.60, 24.61, 36.10, 37.71, 41.73, 42.13, 67.70,
68.62, 76.46, 118.10, 134.26.
3.18. 1,9-Dichlorophenazine 19
Compound 19 was prepared as reported.17 Mp 212°C (toluene); lit.17 mp 208–209°C (MeOH); Rf=0.20
(silica gel TLC, 14% EtOAc in hexane); IR (KBr) 3750, 3660, 3100, 1690, 1620, 1540, 1500, 1470, 1420,
1300, 960, 880, 830, 760, 660 cm−1; 1H NMR (500 MHz) δ 7.80 (t, J=8 Hz, 2H), 8.00 (d, J=8 Hz, 2H),
8.18 (d, J=8 Hz, 2H); 13C NMR (125 MHz) δ 128.77, 130.59, 130.88, 134.12, 140.15, 144.32.
3.19. (2S,12S)-(+)-7-(2-Propenyl)-4,10-dioxatridecane-2,12-diol (S,S)-22
Diol (S,S)-22 was prepared as described above for diol (S,S)-17 starting from diol 34 (1.73 g, 12 mmol)
and tosylate (S)-38 (9.8 g, 31 mmol). The crude product was purified by chromatography on silica gel
using 14% acetone in CH2Cl2 as an eluent to give (S,S)-22 (1.87 g, 60%) as a colorless oil. Rf=0.18
(silica gel TLC, 14% acetone in CH2Cl2); [α]25=+24.2 (c 4.082, CH2Cl2); IR (film) 3600–3100 (broad),
D
3080, 2990, 2950, 2890, 2880, 1640, 1470, 1450, 1380, 1330, 1100, 1000, 910, 860 cm−1; 1H NMR (500
MHz) δ 1.13 (d, J=6 Hz, 3H), 1.14 (d, J=6 Hz, 3H), 1.56–1.61 (m, 4H), 1.76–1.78 (m, 1H), 2.07 (t, J=7
Hz, 2H), 3.00 (broad s, 2H), 3.20–3.57 (m, 8H), 3.94–3.97 (m, 2H), 5.01–5.04 (m, 2H), 5.74–5.79 (m,
1H); 13C NMR (125 MHz) δ 18.52, 31.52, 33.14, 33.17, 38.55, 66.22, 66.29, 69.10, 69.26, 76.51, 76.74,
116.43, 136.59.
3.20. (2S,12S)-(+)-7,7-Bis(2-propenyl)-4,10-dioxatridecane-2,12-diol (S,S)-23
Diol (S,S)-23 was prepared as described above for diol (S,S)-17 starting from diol 35 (2.21 g, 12 mmol)
and tosylate (S)-38 (9.8 g, 31 mmol). The crude product was purified by chromatography on silica gel
using 14% acetone in CH2Cl2 as an eluent to give (S,S)-23 (2.88 g, 80%) as a colorless oil. Rf=0.22
(silica gel TLC, 14% acetone in CH2Cl2); [α]25=+20.2 (c 2.021, CH2Cl2); IR (film) 3600–3100 (broad),
D
3080, 2980, 2920, 2900, 2870, 1640, 1480, 1450, 1370, 1320, 1100, 1000, 910, 840 cm−1; 1H NMR (500
MHz) δ 1.11 (d, J=6 Hz, 6H), 1.60 (t, J=7 Hz, 4H), 1.92–2.03 (m, 4H), 3.17–3.55 (m, 8H), 3.24 (broad

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
s, 2H), 3.92–3.95 (m, 2H), 5.02–5.08 (m, 4H), 5.75–5.82 (m, 2H); 13C NMR (125 MHz) δ 18.64, 36.08,
37.68, 41.70, 66.53, 67.64, 77.15, 118.08, 134.22.
3.21. 2,2-Bis(2-propenyl)-propane-1,3-diol 27
To a well-stirred mixture of LiAlH4 (9.1 g, 0.24 mol) in dry and pure ether (140 mL) was added
dropwise at 0°C and under Ar diethyl diallylmalonate 25 (24 g, 0.1 mol) dissolved in ether (150 mL). The
reaction mixture was stirred at 0°C for 30 min, at room temperature for 30 min, and at reflux temperature
for 12 h, then it was cooled down to 0°C and aqueous saturated NH4Cl (9 mL) followed by 5% aqueous
NaOH (18 mL) were added very slowly. The resulting mixture was stirred at room temperature for 30
min, then at reflux temperature for 14 h. The white precipitate was filtered off and washed thoroughly
with ether (5×50 mL). Filtrate and washings were combined and this ethereal solution was dried over
MgSO4, filtered and the solvent was evaporated. Traces of water from the residue were removed as
described above for (S,S)-17 using toluene. The crude product was purified by distillation to give 27
(14.5 g, 93%) as a clear oil. Bp 88–89°C (0.1 mmHg). All other physical properties and spectroscopic
data were identical to diol 27 prepared by a different procedure described in the literature.28
3.22. 2-(2-Propenyl)-propane-1,3-diol di-p-tosylate 28
To a well-stirred mixture of finely powdered KOH (26.4 g, 85%, 0.4 mol) in THF (40 mL) was added
dropwise at 0°C and under Ar diol 26 (5.81 g, 0.05 mol) and tosyl chloride (26.7 g, 0.14 mol) dissolved
together in THF (160 mL). The resulting mixture was stirred at 0°C for 2 h, then it was allowed to
warm up to room temperature and stirring was continued at room temperature for 4 h. The solvent was
evaporated at room temperature, and the residue was taken up in ice-water (300 mL) and CH2Cl2 (800
mL). The aqueous phase was extracted with CH2Cl2 (3×200 mL). The combined organic phase was
shaken with distilled water (400 mL), dried over MgSO4, filtered and evaporated. The crude product was
recrystallized from EtOH to give 28 (20.1 g, 97%) as white crystals identical in every aspect to tosylate 28
prepared by the reported procedure.29 Rf=0.50 (silica gel TLC, 33% EtOAc in hexane); IR (KBr) 3080,
3050, 3030, 3000, 2970, 2920, 1640, 1610, 1500, 1480, 1460, 1400, 1380, 1210, 1190, 1100, 1030, 990,
930, 860, 830, 800, 690, 600, 570 cm−1; 1H NMR (80 MHz) δ 1.88–2.18 (m, 3H), 2.45 (s, 6H), 3.92 (d,
J=6 Hz, 4H), 4.78–5.05 (m, 2H), 5.28–5.81 (m, 1H), 7.30 (d, J=8 Hz, 4H), 7.73 (d, J=8 Hz, 4H).
3.23. 2,2-Bis(2-propenyl)-propane-1,3-diol di-p-tosylate 29
Ditosylate 29 was prepared as described above for ditosylate 28 using diol 27 (7.8 g, 0.05 mol). The
crude product was recrystallized from MeOH to give 29 (21.6 g, 97%) as white crystals. Mp 71°C
(MeOH); Rf=0.55 (silica gel TLC, 33% EtOAc in hexane); IR (KBr) 3080, 3050, 3030, 2980, 2950,
1
2910, 2840, 1640, 1590, 1490, 1470, 1380, 1180, 1090, 960, 930, 830, 810, 790, 670, 550 cm−1; H
NMR (80 MHz) δ 1.98 (d, J=7 Hz, 4H), 2.45 (s, 6H), 3.78 (s, 4H), 4.81–5.18 (m, 4H), 5.28–5.84 (m,
2H), 7.31 (d, J=8 Hz, 4H), 7.75 (d, J=8 Hz, 4H).
3.24. 3-(2-Propenyl)-glutaronitrile 30
A mixture of 2-(2-propenyl)-propan-1,3-diol di-p-tosylate 28 (25.5 g, 0.06 mol), NaCN (11.7 g, 0.24
mol) and DMSO (160 mL) was stirred at room temperature for 10 min then at 75°C for 18 h. The reaction
was cooled to room temperature and was taken up in ice-water (300 mL) and ether (500 mL). The aqueous

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2793
phase was extracted with ether (2×300 mL). The aqueous phase containing NaCN was treated with an
excess of 20% aqueous FeSO4 solution to cease its toxicity. The combined organic phase was shaken
with ice-cold water (500 mL), and saturated brine (250 mL), dried over MgSO4, filtered and evaporated.
Traces of water from the residue were removed as described above for (S,S)-17 using toluene. The crude
product was purified by fractional distillation to give 30 (7.1 g, 88%) as a colorless oil. Bp 76°C (0.2
mmHg); Rf=0.44 (silica gel TLC, 9% 2-butanone in toluene); IR (film) 3080, 3050, 3030, 2990, 2940,
1
2850, 2240, 1640, 1440, 1420, 990, 920, 840 cm−1; H NMR (80 MHz) δ 2.18–2.40 (m, 3H), 2.55 (d,
J=6 Hz, 4H), 5.00–5.32 (m, 2H), 5.42–5.96 (m, 1H).
3.25. 3,3-Bis(2-propenyl)-glutaronitrile 31
Dinitrile 31 was prepared as described above for dinitrile 30 using ditosylate 29 (27.3 g, 0.06 mol).
Chromatography on silica gel using 20% acetone in hexane as an eluent, then triturating the product with
hexane gave 31 (5.0 g, 48%) as white crystals. Mp 37°C (hexane); Rf=0.18 (silica gel TLC, 20% acetone
in hexane); IR (KBr) 3080, 3050, 3030, 3000, 2980, 2950, 2930, 2920, 2870, 2850, 2240, 1640, 1440,
1420, 1000, 930, 840, 630 cm−1; 1H NMR (80 MHz) δ 2.26 (d, J=7 Hz, 4H), 2.34 (s, 4H), 5.05–5.41 (m,
4H), 5.48–6.04 (m, 2H).
3.26. 3-(2-Propenyl)-glutaric acid 32
A mixture of nitrile 30 (13.4 g, 0.1 mol), MeOH (600 mL) and 35% (w/w) aqueous NaOH (250 g)
was stirred at reflux temperature for 10 h. Most of the MeOH was removed by distillation at atmospheric
pressure and the resulting aqueous mixture was refluxed for 4 h, then cooled to 0°C and it was made
acidic with 37% aqueous HCl (pH=2). Diacid 32 was extracted with EtOAc (3×400 mL). The combined
organic phase was dried over MgSO4, filtered and evaporated. Traces of water from the residue were
removed as described above for (S,S)-17 using toluene. The crude product was purified by distillation to
give pure 32 (16.2 g, 94%) which solidified after standing. Bp 150–152°C (0.2 mmHg); mp 28–30°C;
Rf=0.35 (silica gel TLC, 8% acetic acid and 8% acetone in toluene); IR (KBr) 3600–2300 (broad), 1700,
1640, 1440, 1410, 1290, 1230, 990, 910, 860 cm−1; 1H NMR (80 MHz) δ 2.05–2.28 (m, 3H), 2.30–2.52
(m, 4H), 4.84–5.22 (m, 2H), 5.42–6.02 (m, 1H), 10.92 (broad s, 2H).
3.27. 3,3-Bis(2-propenyl)-glutaric acid 33
Diacid 33 was prepared as described above for diacid 32 starting from dinitrile 31 (5.22 g, 0.03 mol).
The crude product was purified by crystallization from toluene to give 33 (6.1 g, 96%) as white crystals.
Mp 111°C (toluene); Rf=0.44 (silica gel TLC, 8% acetic acid and 8% acetone in toluene); IR (KBr)
1
3600–2300 (broad), 1700, 1640, 1440, 1400, 1320, 1280, 1210, 1180, 990, 930, 910, 620 cm−1; H
NMR (80 MHz, DMSO-d6) δ 2.16 (d, J=7 Hz, 4H), 2.32 (s, 4H), 4.84–5.21 (m, 4H), 5.57–6.18 (m, 2H),
11.95 (broad s, 2H).
3.28. 3-(2-Propenyl)-pentane-1,5-diol 34
To a well-stirred mixture of LiAlH4 (5.7 g, 0.15 mol) in dry and pure ether (200 mL) was added
dropwise at 0°C and under Ar diacid 32 (8.60 g, 0.05 mol) dissolved in ether (250 mL). The reaction
mixture was stirred at 0°C for 30 min, at room temperature for 30 min, then at reflux temperature for 24
h. The reaction mixture was cooled down to 0°C and aqueous saturated NH4Cl (6 mL) then 5% aqueous

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E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
NaOH (12 mL) were added very slowly. The resulting mixture was stirred at room temperature for 30
min, then at reflux temperature for 10 h. The white precipitate was filtered off and washed throughly
with ether (5×50 mL). Filtrate and washings were combined and this ethereal solution was dried over
MgSO4, filtered and the solvent was evaporated. Traces of water from the residue were removed as
described above for (S,S)-17 using toluene. The crude product was purified by distillation to give 34
(6.34 g, 88%) as a clear oil. Bp 96–98°C (0.2 mmHg); Rf=0.25 (silica gel TLC, 14% EtOH in toluene);
IR (film) 3650–3100 (broad), 3080, 3030, 2980, 2940, 2870, 2850, 1640, 1440, 1060, 1000, 900 cm−1;
1H NMR (80 MHz) δ 1.55 (t, J=7 Hz, 4H), 1.58–1.98 (m, 1H), 2.09 (t, J=7 Hz, 2H), 3.41 (broad s, 2H),
3.61 (t, J=7 Hz, 4H), 4.82–5.18 (m, 2H), 5.52–6.03 (m, 1H).
3.29. 3,3-Bis(2-propenyl)-pentane-1,5-diol 35
Diol 35 was prepared as described above for diol 34 using diacid 33 (10.6 g, 0.05 mol). Chromato-
graphy on silica gel using 9% EtOH in toluene as an eluent, then triturating the product with hexane gave
35 (8.65 g, 94%) as white crystals. Mp 40°C (hexane); Rf=0.30 (silica gel TLC, 14% EtOH in toluene);
IR (KBr) 3650–3100 (broad), 3080, 3030, 2950, 2940, 2920, 2870, 1640, 1440, 1050, 1020, 1000, 900
cm−1; 1H NMR (80 MHz) δ 1.58 (t, J=7 Hz, 4H), 2.05 (d, J=7 Hz, 4H), 2.72 (broad s, 2H), 3.71 (t, J=7
Hz, 4H), 4.83–5.18 (m, 4H), 5.51–6.08 (m, 2H).
3.30. (S)-(−)-2[(Tetrahydro-2H-pyran-2-yl)oxy]-propan-1-ol p-tosylate (S)-38
Tosylate (S)-38 was prepared as reported21 starting from alcohol (S)-36 (16.0 g, 0.1 mol). The crude
product was purified by chromatography on silica gel using 2% acetone in toluene as an eluent to give
(S)-38 (28.6 g, 91%) as a mixture of two diastereomers. Rf=0.25 (silica gel TLC, 3% acetone in toluene);
[α]25=−3.0 (c 2.90, CH2Cl2); IR (film) 3080, 3050, 3030, 2980, 2950, 2930, 2900, 2870, 1600, 1500,
D
1
1460, 1360, 1180, 1170, 1120, 1070, 1030, 1010, 970, 800, 660 cm−1; H NMR (80 MHz) δ 1.08 and
1.18 (d, J=6 Hz, 3H), 1.32–1.94 (m, 6H), 2.43 (s, 3H), 3.22–4.15 (m, 5H), 4.52–4.68 (m, 1H), 7.29 (d,
J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H).
3.31. (S)-(−)-4-Methyl-2[(tetrahydro-2H-pyran-2-yl)oxy]-pentan-1-ol p-tosylate (S)-39
Tosylate (S)-39 was prepared in the same way as described for tosylate (S)-38 in the literature21 starting
from alcohol (S)-3730 (20.2 g, 0.1 mol). The crude product was purified by chromatography on silica gel
using 1% acetone in toluene as an eluent to give (S)-39 (32.8 g, 92%) as a mixture of two diastereomers.
Rf=0.40 (silica gel TLC, 3% acetone in toluene); [α]25=−25.0 (c 1.353, CH2Cl2); IR (film) 3080, 3050,
D
3030, 2970, 2940, 2880, 1600, 1500, 1480, 1470, 1370, 1200, 1190, 1140, 1100, 1080, 1040, 990, 810,
670 cm−1; 1H NMR (80 MHz) δ 0.92 (d, J=6 Hz, 6H), 1.16–1.83 (m, 9 H), 2.45 (s, 3H), 3.21–4.27 (m,
5H), 4.52–4.72 (m, 1H), 7.32 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H).
Acknowledgements
Financial support by the Hungarian Scientific Research Fund (OTKA T-14942, T-22913 and T-25071)
is gratefully acknowledged.

E. Samu et al. / Tetrahedron: Asymmetry 10 (1999) 2775–2795
2795
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