Synthesis and structural analysis of new macrocycles exhibiting 3,9-dimethyl-3,9-diaryl-2,4,8,10-tetraoxaspiro[5.5]undecane units

Article abstract of DOI:10.1016/j.tet.2004.04.002

The template synthesis of a new series of macrocycles (from monomers to tetramers) with 2,4.8,10-tetraoxaspiro[5.5]undecane units is reported. The structural analysis of the compounds is carried out using the data of high field NMR investigations, mass spectrometry studies (FAB, MALDI and ESI-MS) and the solid state X-ray diffractometry molecular structures for three compounds.

Full text of DOI:10.1016/j.tet.2004.04.002

Tetrahedron 60 (2004) 4789–4799
Synthesis and structural analysis of new macrocycles exhibiting
3,9-dimethyl-3,9-diaryl-2,4,8,10-tetraoxaspiro[5.5]undecane units
†
a
Gerard Ple, Yvan Ramondenc, Loıc Toupet,
a
c
Mirela Balog,a,b Ion Grosu,a,b
, ,
*
´
Eric Condamine, Catherine Lange, Corinne Loutelier-Bourhis, Valerie Peulon-Agasse
´
¨
a
a
a
a
´
and Elena Bogdanb
a
´
´
Faculte des Sciences, Universite de Rouen, IRCOF, UMR 6014, 76821 Mont Saint-Aignan, Cedex, France
bOrganic Chemistry Department and CSOFSTM, Babes-Bolyai University, 11 Arany Janos str., RO-400028 Cluj-Napoca, Romania
´
Universite de Rennes 1, UMR C-6626, Campus de Beaulieu, Bat. 11A, 35042 Rennes, Cedex, France
c
Received 25 January 2004; revised 5 March 2004; accepted 1 April 2004
Abstract—The template synthesis of a new series of macrocycles (from monomers to tetramers) with 2,4.8,10-tetraoxaspiro[5.5]undecane
units is reported. The structural analysis of the compounds is carried out using the data of high field NMR investigations, mass spectrometry
studies (FAB, MALDI and ESI-MS) and the solid state X-ray diffractometry molecular structures for three compounds.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The development of the synthesis and structural analysis
of macrocycle compounds includes the use of this type of
derivatives in chiral recognition processes, in the discrimi-
nation and separation of enantiomers and in the catalysis of
enantioselective reactions.1 The synthesis of macrocycles
with enantioselective and enantiospecific supramolecular
proprieties is based on chiral substrates in many cases
Scheme 1.
proceeding from natural compounds. The macrocyclisation
of sugars (e.g., with polyethyleneglycols) leads to crown
ethers exhibiting high coordination ability and selec-
tivity.2–8 In order to obtain compounds with similar
proprieties but with various cavities and coordination
abilities some peculiar chiral substrates as bicyclo and
spiro derivatives of saturated heterocycles with six-
membered rings were successfully used.9–20 Important
features in high yield macrocyclisation reactions are the
geometry of the substrate, which has to exhibit the pre-
organization required by the incorporation in the macro-
cycle, and the high number of heteroatoms which can
coordinate to cations and are able to promote the
macrocyclisation by the template effect.21 In order to
identify suitable substrats for macrocyclization, we ana-
lyzed the stereochemistry of spiro-1,3-dioxane derivatives
(I and II) exhibiting 2,4,8,10-tetraoxaspiro[5.5]undecane
skeleton and aromatic substituents (phenol groups) at the
extremities (positions 3 and 9) of the spirane (Scheme 1).
The spirane skeleton (I–II) is chiral and shows the
characteristic helical and axial chirality of spiro compounds
with six-membered rings22–24 and the two 1,3-dioxane rings
of the spirane exhibit a favorable angular orientation. The
six-membered rings are anancomeric, the substituents in
the acetal part of the 1,3-dioxane ring have high A-values
and are efficient ‘holding groups’.25 The stereochemistry of
these compounds (I and II) is different if the aromatic groups
are the unique substituents at positions 3 and 9 (R¼H, I) or
if besides the aromatic substituents, methyl groups are also
located at the same positions (R¼CH3, II). These differ-
ences were previously observed in the investigations on
the more simple structures of 2-aryl-1,3-dioxanes III and
2-alkyl,2-aryl-1,3-dioxanes IV. In the first case (Scheme 2)
the aromatic groups, due to their high A-values (e.g.,
APh¼3.12 kcal/mol),26 prefer the equatorial orientation
(conformer IIIA), while in the second case the con-
formational equilibrium is strongly shifted towards the
conformer exhibiting the aromatic substituent in axial
Keywords: Macrocycle; Spiro-1,3-dioxane; X-ray diffractomatry; ESI-MS;
Ditopic ligand.
*
Corresponding author. Tel.: þ40-26459-3833; fax: þ40-26459-0818;
e-mail address: igrosu@chem.ubbcluj.ro
Present address: Organic Chemistry Department and CSOFSTM, Babes-
†
Bolyai University, 11 Arany Janos str., RO-400028 Cluj-Napoca,
Romania.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.002

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M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
In a recent work29 the efficient synthesis of new coronands
of various sizes (monomers and dimers) with equatorial–
equatorial cyclisation in the macrocycles, starting from
3,9-di(meta-hydroxyphenyl)-2,4,8,10-tetraoxaspiro[5.5]-
undecane and derivatives of different polyethyleneglycols
(from mono to hexa) was reported.
In this work we describe the design, synthesis, NMR, single
crystal X-ray diffraction based analysis and the ESI-MS
investigations of a series of macrocycles (with axial–axial
connection) obtained from spiro-1,3-dioxanes 3 and 4
(Scheme 3) bearing axial aryl groups at the extremities of
the spirane. The starting spiranes 3 and 4 were obtained30 by
usual procedures31 using the acetalisation of pentaerythritol
with protected hydroxyketones (Scheme 3).
Scheme 2.
orientation (IVA). The preference of the aromatic group for
the axial orientation in this case is about three times higher
(Ar¼C6H5; DG8IVB–IVA¼2.43 kcal/mol)26 than calculated
using the A-values of methyl and phenyl groups
(DG8calcd¼AMe2APh¼3.9823.12¼0.86 kcal/mol).25
The axial disposition of the aromatic groups in the target
macrocycles determines a peculiar behavior and shape for
the created cavities. The structural differences among the
macrocycles with axial–axial connection of the spirane
units and of those with equatorial–equatorial connection of
the spirane skeleta (previously reported29) determine a
priori differences among the ability and the selectivity of the
possible complexation processes involving the two types of
macrocycles and motivate the interest for this work.
In agreement with these data and with the results of the
investigations on the stereochemistry of similar spirane
derivatives27,28 the equatorial orientation of both aromatic
groups in compounds I and the axial orientation of the
aromatic substituents in compounds II was predicted. The
enclosure of macrocycles (promoted by the orientation of
the 1,3-dioxane rings of the spirane) starting from I is
performed by the connection of equatorial groups (equa-
torial–equatorial connection) of the starting substrate, while
the macrocyclisation of compounds II occurs between the
axial substituents of the substrate (axial–axial connection).
The macrocyclisation of I and II leads to cavities with
different dimensions and geometries.
2. Results and discussion
New macrocycles 5-11 exhibiting spirane units were
obtained by the cyclisation of compounds 3 and 4 with
several ditosylated polyethyleneglycols (Scheme 4).
Scheme 3.
Scheme 4.

M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
Table 1. Results in the synthesis of macrocycles 5-11
4791
Compound
N
Isomer
Global yieldsa
Observed macrocycles (yields, %, of separated terms)
5
6
7
8
9
10
11
2
3
4
5
6
2
3
para
para
para
para
para
meta
meta
53
34
41
56
61
27
32
Dimer (24), trimer, tetramer (2)
Dimer (34)
Monomer (6), dimer (18), trimer, tetramer
Monomer (20), dimer (22), trimer, tetramer
Monomer (17), dimer (15), trimer, tetramer
Dimer (27)
Monomer (15), dimer (17)
a
The global yields were calculated using the amounts of macrocycles, single terms and mixture of terms, isolated by flash-chromatography.
The reactions were performed in good yields (27–61%,
Table 1), using Cs2CO3 as base and template and
acetonitrile as solvent.
different size macrocycles can be correlated with the lengths
of the polyethyleneglycol chains and with the para or meta
positions of the reacting groups on the aromatic rings. In the
para series if the chain is long enough (n¼4–6) all the rings
are formed (monomer–tetramer). The monomers and the
dimers are obtained in comparable amounts and they are the
main products of the reactions. In the meta series for n¼2
only the dimer macrocycle was formed, while for the longer
chain (n¼3) the crude product exhibits monomer and dimer
compounds in comparable amounts.
The reactions gave rise to monomer, dimer, trimer and
tetramer macrocycles (proved by mass spectrometry). The
mixtures were very complex. However, after many
chromatography separations all the monomers and all the
dimers could be isolated as single compounds and their
structures could be determined using high field NMR (500
and 600 MHz) spectroscopy, mass-spectrometry (FAB,
MALDI and ESI-MS) and single crystal X-ray diffracto-
metry. The tetramer 5d was also isolated as a single
compound, but in the other cases of larger cycles (trimers
and tetramers) column chromatography separations led only
to enriched mixtures of the target compounds. Because
during the chromatography separations many fractions
containing mixtures of compounds were collected, a
quantitative appreciation of the ratios of different com-
pounds could not be calculated. HPLC investigations for
compounds 8 and 9 made it possible to establish the ratios of
monomers, dimers and trimers in the crude products. For 8
the ratio monomer (tR(m)¼4.7 min)/dimer (tR(d)¼8.2 min)/
trimer (tR(t)¼16.2 min) is 48/44/8, while the ratio of
monomer (tR(m)¼5.3 min)/dimer (tR(d)¼9.6 min)/trimer
(tR(t)¼20.6 min) in the case of compound 9 was found to
be 50/45/5.
2.1. Solid state molecular structures
The molecular structures for monomers 8a, 9a and for dimer
5b were obtained by single crystal X-ray diffractometry.
The ORTEP diagrams (Figs. 1–3) show the axial orthogo-
nal orientation of all aromatic rings. The orthogonal
disposition of the aromatic rings is deduced from the values
of the dihedral angles formed by the aromatic rings and the
best plane of the corresponding 1,3-dioxane rings (Table 2).
The X-ray diffractometry investigations for 9a revealed the
presence in the crystal of two different molecules (with
close structures). Each macrocycle exhibits a molecule of
water included in its cavity and shows a disorder of the part
of the chain involved in the fixation of water. The distances
from the oxygen atom of the included molecule of water to
the closer oxygen atom of the chain are of d¼2.598 and
˚
The preference in the macrocyclisation reaction for the
2.781 A, respectively and suggest the fixation of water by
Figure 1. ORTEP diagram of compound 8a.

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M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
Figure 2. ORTEP diagram of compound 9a.
Figure 3. ORTEP diagram of compound 5b.
Table 2. Values (8) of specific dihedral angles for the rotameric behavior of aromatic rings in solid state for compounds 8a, 9a and 5b
Compound
Dihedral angles
Values
Rotamersa
8a
9a
5b
C18C19C20C21C32C33/C21C22C40
C1C29C30C31C38C39/C28C29C41
82.4(4)
80.4(4)
86.7(8)
88.5(7)
81.5(1)
81.3(1)
80.9(4)
80.7(5)
orthogonal
orthogonal
orthogonal
orthogonal
orthogonal
orthogonal
orthogonal
orthogonal
C
21C22C23C24C35C36/C24C25C43
C1C32C33C34C41C42/C31C32C44
C
31C32C33C34C53C54/C34C35C63
C1C42C43C44C59C60/C41C42C64
C9C10C11C12C45C46/C12C13C61
C
20C21C22C23C51C52/C19C20C62
a
Values of the dihedral angles close to 08 correspond to the bisectional rotamers and values close to 908 correspond to orthogonal rotamers.

M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
4793
hydrogen bonds (the positions of the hydrogen atoms of the
water could not be determined with precision).
The diastereoisomers of the majority of the dimers could
be discriminated in NMR spectra. The spectra of these
compounds exhibit two sets of signals, belonging to the like
and unlike isomers. Starting from the relative intensities of
the well separated peaks (aromatic protons and methyl
groups) the ratios of the two stereoisomers (D1/D2) could be
calculated for the para series (compounds 5-9):5b (60/40);
6b (55/45); 7b (55/45); 8b (50/50) and 9b (55/45). The
results prove the obtaining of the two diastereoisomers (like
and unlike) in close amounts. The 1H and 13C NMR spectra
of tetramer 5d cannot discriminate the different stereo-
isomers and exhibit unique sets of signals. The shape of the
spectra for the different cycles (from monomers to
tetramers) are close and generally show the same type of
The investigated crystal of compound 5b belongs to the like
isomer (the ORTEP diagram represents the PP isomer). The
crystal cell is centrosymmetric and the compound is a
racemate.
The aromatic rings (5b) exhibit a peculiar arrangement
close to the T-structure (edge-to-face)32 suggesting impor-
tant p-stacking interactions. The dihedral angles formed
by the involved aromatic rings are close to 908
(C20C21C22C23C51C52/C31C32C33C34C53C54¼81.38 and
C9C10C11C12C45C46/C1C42C43C44C59C60¼78.38) and the
distances from the center of an aromatic ring to the center
1
signals. Despite this similarity of the H NMR spectra the
˚
of the opposite aromatic ring are 5.489 and 5.763 A,
parts of the spectra of monomers belonging to the protons of
the chain display a peculiar pattern. The magnetic
anisotropy of the phenylene groups (exhibiting a limitation
of their rotation in monomers) and the peculiar orientation
of the chain determine significantly different magnetic
environments for the protons of the marginal ethyleneoxyde
groups (connected to the aromatic rings) and the recording
for these protons of four different signals (doublet of
doublets of doublets). The diastereotopicity for the a
protons (Dd¼0.15–0.18 ppm) is higher than the dia-
respectively. The values of distances from H52 and H60 to
˚
the centers of the opposite aromatic rings (3.34 and 3.76 A)
support the consideration of significant intramolecular
stacking interactions in 5b. These intramolecular inter-
actions explain the peculiar deformed shape of this
macrocycle
2.2. Stuctural aspects in solution
1
The monomeric macrocycles are obtained as racemic (M or
P configuration of the helix belonging to the spirane units),
while the higher termes are obtained as mixtures of
diastereoisomers. The dimers exhibit like (PP, MM) and
unlike (PM) isomers. The components of the mixtures of
isomers obtained for the dimers were denoted as D1 (major)
and D2 (minor) because their assignment to like and unlike
structures could not be completed. Two diastereoisomers
(both chiral; D3: MMM, PPP and D4: MPP, PMM) are
possible for the trimer and the tetramer shows four
diastereoisomers (D5: MMMM, PPPP; D6: MPPP,
PMMM; D7: PPMM and D8: PMPM), two of them (D7
and D8) being achiral. The different size cycles (monomers,
dimers and the tetramer 5d) were isolated as mixtures of
stereoisomers.
stereotopicity for the b protons (Dd,0.10 ppm). The H
NMR spectra of the dimers and of the tetramer 5d exhibit
for the same types of protons only two signals, both a and b
protons give (pseudo)triplets.
In order to assess the complexing abilities of the new
macrocycles (for the cations of the first group) an ESI-MS
study was developed with compounds 8a, 9a and 5b-9b.
The samples were prepared by mixing in volume ratios of 2/
1, 1/1 and 1/2 the solution of macrocycle (1026 M) with the
solution containing equimolecular amounts (1026 mol/l) of
LiI, NaI, KI, RbI and CsI. The experiments were carried out
at several cone voltages (17, 20, 25, 38 and 72 V). In all
cases a high preference for the complexes with Naþ (8a, 9a,
5b and 6b) or Kþ (7b-9b) was observed.
Figure 4. ESI-MS spectrum of compound 9a obtained at a cone voltage of 17 V and at a ratio macrocycle:salts of 1:2.

4794
M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
Table 3. ESI-MS data (ditopic complexation) of compound 9a obtained at a cone voltage of 17 V and at a ratio macrocycle:salts of 1:2
Ions
Mþ2Hþ Mþ2Liþ Mþ2Naþ Mþ2Kþ MþLiþþHþ MþLiþþNaþ MþNaþþKþ MþNaþþRbþ MþLiþþCsþ MþNaþþCsþ
Relative
intensities (%)
7.5
7.5
25
20
7.5
50
12.5
12.5
15
15
Even if these results are not spectacular and confirm the
high ability of crown-ethers for the complexation with Naþ
and Kþ some of the experiments revealed interesting
aspects. The ESI-MS spectra at low cone voltage and at
the ratio macrocycle/salts¼1/2 showed the capacity of the
investigated compounds to coordinate as ditopic ligands
(e.g., compound 9a, Fig. 4, Table 3).
complexation ability in the second step when the cone
voltage is brought at 78 V. This result is explained by the
breaking at high cone voltage of the intramolecular
interactions of the macrocycle and the production of larger
cavities able to coordinate higher sizes cations (Kþ, Rbþ
and Csþ).
An interesting feature was observed concerning the ability
of macrocycles 8a, 9a and 5b to coordinate Csþ. In an
unexpected manner the complexation capacity of the
mentioned macrocycles for this cation increases at high
cone voltage. As an example, the experiments carried out
with compound 8a, (Fig. 5) showed a dramatic modification
of the relative intensity for the [MþCs]þ peak with the
modification of the cone voltage (25 V: 12%; 38 V: 8% and
72 V: 98%). In a similar way at higher cone voltage the
complexation ability of 8a for Kþ (25 V: 32%; 38 V: 12%:
and 72 V: 67%). and Rbþ, (25 V: 7%; 38 V: 3%: and 72 V:
31%) is also increased. It can be observed for the
complexation of 8a with all mentioned cations a lowering
of the complexation ability in the first step, when the cone
voltage is increased from 25 to 38 V (an expected result)
and in an unexpected way a dramatic increasing of the
3. Conclusions
The template synthesis of new macrocycles leads to the
obtaining in good yields of different size coronands
(different lengths of the chain and different terms: from
monomers to tetramers). The structural analysis performed
on 13 isolated macrocycles (5 monomers, 7 dimers and one
tetramer) using high field NMR, mass-spectrometry and
X-ray diffractometry investigations reveals the axial
orientation of the aromatic substituents, the stacking
interactions between the aromatic rings and the inclusion
of a molecule of water in the cavity of the monomer
macrocycle with six ethyleneoxyde units. The ESI-MS
study shows the preference of these macrocycles for the
coordination of Naþ and Kþ but also points out their
capacity to coordinate as ditopic ligands.
Figure 5. ESI-MS spectra of compound 8a obtained at a ratio macrocycle:salts of 1:1 and at different cone voltages: 25 V (a), 38 V (b), 72 V (c).

M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
4795
4. Experimental
C25H28O8 requires: C, 65.78; H, 6.18); dH (3000M0 Hz;
CDCl3) 1.46 (6H, s, 3-CH3, 9-CH3), 2.29 [6H, s, 40(4 )-O–
CO–CH3], 3.15 (2H, dd, J¼11.3, 1.8 Hz, 5-Heq, 7-Heq),
3.24 (2H, d, J¼11.3 Hz, 5-Hax, 7-Hax), 3.59 (2H, d, J¼
10.9 Hz, 1-Hax, 11-Hax), 4.42 (2H, d, J¼10.9 Hz, 1-Heq,
11-Heq), 7.09 (4H, d, J¼8.4 Hz, 30-H, 50-H, 300-H, 500-H),
7.39 (d, 4H, J¼8.4 Hz, 20-H, 60-H, 200-H, 600-H,). dC
(75 MHz; CDCl3) 21.57 [40(400)-O–CO–CH3], 32.20
(3-CH3, 9-CH3), 32.76 (6-C), 65.03 (5-C, 7-C), 65.36
(1-C, 11-C), 101.19 (3-C, 9-C), 122.25 (30-C, 50-C, 300-C,
500-C), 128.24 (20-C, 60-C, 200-C, 600-C), 138.21 (10-C, 100-C),
150.65 (40-C, 400-C), 169.85 [40(400)-O–CO–CH3].
NMR spectra [1H (600 or 500 MHz), 13C (150 or 125 MHz),
COSY, APT, HETCOR (HMBC, HSQC), NOESY or
ROESY)] were recorded at rt, in C6D6 or CDCl3. Melting
points are uncorrected. Microanalyses (C, H) agreed (inside
^0.2%) with calculated data. FAB and MALDIþ spectra
were obtained on a JEOL JMS AX-500 spectrometer under
usual conditions.
Electrospray ionisation mass spectra (ESI-MS) were
recorded on a five-sector mass spectrometer Micromass
Autospec-T of EBEBE geometry (where B is a magnetic
sector and E is an electric sector) equipped with an
atmospheric pressure ionization source and Opus V3.5X
data system (Micromass, Manchester, UK). The samples
were flow injected at 5 ml/min by means of a syringe pump
(Havard Apparatus, model 11) into a needle operating at
8 kV. The voltages of the sampling cone and skimmer lens
were varied, while the voltage of the skimmer was fixed at
4 kV. Thus, the resulting potential difference was varied
from 17 to 72 V. The temperature of the source was 80 or
40 8C. The nebulization and bath gas were nitrogen
(99.995%). Full scan spectra were recorded in positive
ions mode over the m/z range 3000–400 at a scan rate of
5 s/decade. The resolution was 1500. Calibrations were
carried out using an equimolar mixture of polypropylene
glycols (PPG) 725, 1000, 2000, 3000, 4000 (1025 M).
4.1.2. 3,9-Dimethyl-3,9-di(m-acetyloxyphenyl)-2,4,8,10-
tetraox aspiro[5.5]undecane (2). White crystals (9.56 g,
49%), mp 126–127 8C (Found C, 65.49; H, 6.26; C27H36O8
requires: C, 65.78; H, 6.18); dH (300 MHz; CDCl3) 1.46
(6H, s, 3-CH3, 9-CH3), 2.28 [6H, s, 30(300)-O–CO–CH3],
3.14 (2H, dd, J¼11.6, 2.0 Hz, 5-Heq, 7-Heq), 3.22 (2H, d, J¼
11.6 Hz, 5-Hax, 7-Hax), 3.59 (2H, d, J¼11.6 Hz, 1-Hax,
11-Hax), 4.42 (2H, d, J¼11.6 Hz, 1-Heq, 11-Heq), 7.02 (2H,
dt, J¼7.9, 1.4 Hz, 40-H, 400-H), 7.090(2H, t, J¼1.4 Hz, 20-H,
200-H); 7.25–7.27 (2H, multiplet, 6 -H, 600-H); 7.38 (2H, t,
J¼7.9 Hz, 50-H, 500-H) dC(75 MHz; CDCl3) 21.56 [30(300)-
O–CO–CH3], 32.04 (3-CH3, 9-CH3), 32.66 (6-C), 65.10
(5-C, 7-C), 65.43 (1-C, 11-C),00101.03 (3-C, 9-C), 120.43
(40-C, 400-C), 121.52 (20-C, 2 -C), 124.45 (60-C, 600-C),
130.23 (50-C, 5000-C), 142.72 (10-C, 100-C), 151.61 (30-C,
300-C), 169.82 [3 (300)-O–CO–CH3].
X-ray crystallographic data for 8a, 9a and 5b are deposited
CCDC-194713 (8a), 194714 (9a) and 194715 (5b) at
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: (internat.) þ44-1223/336-
033; e-mail: deposit@ccdc.cam.ac.uk] and they can be
obtained free of charge at http://www.ccdc.cam.ac.uk/conts/
retrieving.html.
4.2. General procedure for the synthesis of new
compounds 3 and 4
A solution (200 ml, 1 M) of LiOH in water was added to the
solution (200 ml methanol/THF¼1/1) of 40 mmol com-
pounds 1 or 2 to obtain a cloudy mixture that became
homogeneous after stirring 12 h at rt. The solvents were
removed under reduced pressure and the residue was
dissolved in 100 ml of water. The obtained solution was
acidulated with oxalic acid till pH 8 and then extracted with
2£200 ml diethyl ether. The organic layers were dried over
MgSO4. The ether was removed under reduced pressure
and the pure compounds 3 and 4 were obtained by
crystallization from chloroform.
The HPLC discrimination of different size cycles for 8 and 9
was performed on a C18, Hypersyl (25 cm£4.6 mm, 10 mm)
achiral column, using methanol/water (9/1) as elution
system at a flow rate of 1.00 ml min21. Classic UV 2000
(at l¼230 nm) and ESI-MS detections were used.
4.1. General procedure for the synthesis of new
compounds 1 and 2
4.2.1. 3,9-Dimethyl-3,9-di(p-hydoxyphenyl)-2,4,8,10-
tetraoxa-spiro[5.5]undecane (3). White crystals (7.68 g,
95%), mp 226–227 8C (Found C, 67.54; H, 6.69; C21H24O6
requires: C, 67.73; H, 6.50); dH (300 MHz; C3D6O) 1.38
(6H, s, 3-CH3, 9-CH3), 3.17 (2H, dd, J¼11.6, 2.2 Hz, 5-Heq,
7-Heq), 3.27 (2H, d, J¼11.6 Hz, 5-Hax, 7-Hax), 3.59 (2H, d,
J¼11.3 Hz, 1-Hax, 11-Hax), 4.31 (2H, d, J¼11.3 Hz, 1-Heq,
11-Heq), 6.85 (4H, d, J¼8.6 Hz, 30-H, 50-H, 300-H, 500-H),
7.18 (4H, d, J¼8.6 Hz, 20-H, 60-H, 200-H, 600-H), 8.38 [2H, s,
40(400)-OH] dC (75 MHz; C3D6O) 32.72 (3-CH3, 9-CH3),
33.24 (6-C), 65.50 (50-C, 7-C), 65.80 (1-C, 11-C), 101.93
(3-C, 9-C), 116.68 (3 -C, 500-C, 300-C, 500-C), 129.09 (200 0-C,
60-C, 200-C, 600-C), 132.44 (1 -C, 100-C), 158.23 (40-C, 4 -C).
The corresponding ketone (para or meta acetyloxy-
acetophenone, 90 mmol) and 0.2 g of p-toluenesulphonic
acid were added to a solution of 40 mmol pentaerythritol in
200 ml toluene. The mixture was refluxed and the water
resulting from the reaction was removed using a Dean–
Stark trap. When the theoretical amount of water was
separated, the reaction was cooled at room temperature, and
the catalyst was neutralized (under stirring) with excess
powdered CH3COONa (0.4 g). The reaction mixture is
washed twice with 100 ml water. The organic layer was
dried over Na2SO4, then toluene was removed under
reduced pressure and the spiro compounds were purified
by crystallization from ethanol and dichloromethane (4:1).
4.2.2. 3,9-Dimethyl-3,9-di(m-hydoxyphenyl)-2,4,8,10-
tetraoxa-spiro[5.5]undecane (4). White crystals (7.52 g,
93%), mp 186–187 8C (Found C, 67.92; H, 6.65; C23H32O6
requires: C, 67.73; H, 6.50); dH (300 MHz; CD3OD) 1.32
4.1.1. 3,9-Dimethyl-3,9-di(p-acetyloxyphenyl)-2,4,8,10-
tetraoxa spiro[5.5]undecane (1). White crystals (10.16 g,
52%), mp 176–176.5 8C (Found C, 65.93; H, 6.37;

4796
M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
(6H, s, 3-CH3, 9-CH3), 3.04 (2H, dd, J¼11.8, 2.4 Hz, 5-Heq,
7-Heq), 3.21 (2H, d, J¼11.8 Hz, 5-Hax, 7-Hax), 3.55 (2H, d,
J¼11.6 Hz, 1-Hax, 11-Hax), 4.27 (2H, dd, J¼11.6, 2.4 Hz,
1-Heq, 11-Heq), 6.62 (2H, dt, J¼7.9, 1.4 Hz, 40-H, 400-H),
6.71–6.75 (4H, overlapped peaks, 20-H, 60-H, 200-0H,00600-H);
7.10 (2H, t, J¼7.9 Hz, 50-H, 500-H), 7.80 [2H, s, 3 (3 )-OH]
dC (75 MHz; CD3OD) 32.54 (3-CH3, 9-CH3), 33.35 (6-C),
66.18 (5-C, 7-C), 66.54 (1-C, 11-C), 00102.62 (3-C, 9-C),
114.87 (20-C, 200-C), 116.20 (40-C, 4 -C), 119.06 (60-C,
600-C), 131.31 (50-C, 500-C), 143.46 (10-C, 100-C), 159.53
(30-C, 300-C).
97,103,105,111,113,119-tetracosaene (5d). Colorless
solid, mixture of diastereoisomers, mp 117–119 8C, column
chromatography (after the separation of 5b), (ethylacetate/
heptane¼5/4; Rf¼0.13) 2.0% yield. dH (600 MHz; C6H6)
1.645, 1.649 (s, 24H, 13-CH3, 19-CH3, 35-CH3, 41-CH3,
57-CH3, 63-CH3, 79-CH3, 85-CH3), 2.87 (d, J¼11.6 Hz,
8H, 15-Heq, 17-Heq, 37-Heq, 39-Heq, 59-Heq, 61-Heq, 81-Heq,
83-Heq), 3.13 (d, J¼11.6 Hz, 8H, 15-Hax, 17-Hax, 37-Hax,
39-Hax, 59-Hax, 61-Hax, 81-Hax, 83-Hax), 3.49–3.51 (over-
lapped peaks, 16H, 4-H2, 6-H2, 26-H2, 28-H2, 48-H2, 50-H2,
70-H2, 72-H2), 3.70 (d, J¼11.3 Hz, 8H, 92-Hax, 93-Hax,
100-Hax, 101-Hax, 108-Hax, 109-Hax, 116-Hax, 117-Hax),
3.75–3.77 (overlapped peaks, 16H, 3-H2, 7-H2, 25-H2,
29-H2, 47-H2, 51-H2, 69-H2, 73-H2), 4.69 (d, J¼11.3 Hz,
8H, 92-Heq, 93-Heq, 100-Heq, 101-Heq, 108-Heq, 109-Heq,
116-Heq, 117-Heq), 6.84 (d, J¼8.7 Hz, 16H, 10-H, 22-H,
32-H, 44-H, 54-H, 66-H, 76-H, 88-H, 89-H, 96-H, 97-H,
104-H, 105-H, 112-H, 113-H, 120-H), 7.33 (d, J¼8.7 Hz,
16H, 11-H, 21-H, 33-H, 43-H, 55-H, 65-H, 77-H, 87-H,
90-H, 95-H, 98-H, 103-H, 106-H, 111-H, 114-H, 119-H); dC
(150 MHz; C6D6) 32.98 (16-C, 38-C, 60-C, 82-C), 32.99
(13-C, 19-C, 35-C, 41-C, 57-C, 63-C, 79-C, 85-C), 65.34
(15-C, 17-C, 37-C, 39-C, 59-C, 61-C, 81-C, 83-C), 65.93
(92-C, 93-C, 100-C, 101-C, 108-C, 109-C, 116-C, 117-C),
68.28 (3-C, 7-C, 25-C, 29-C, 47-C, 51-C, 69-C, 73-C),
70.56 (4-C, 6-C, 26-C, 28-C, 48-C, 50-C, 70-C, 72-C),
101.85 (13-C, 19-C, 35-C, 41-C, 57-C, 63-C, 79-C, 85-C),
115.74 (10-C, 22-C, 32-C, 44-C, 54-C, 66-C, 76-C, 88-C,
89-C, 96-C, 97-C, 104-C, 105-C, 112-C, 113-C, 120-C),
129.09 (11-C, 21-C, 33-C, 43-C, 55-C, 65-C, 77-C, 87-C,
90-C, 95-C, 98-C, 103-C, 106-C, 111-C, 114-C, 119-C),
133.71 (12-C, 20-C, 34-C, 42-C, 56-C, 64-C, 78-C, 86-C),
159.63 (1-C, 9-C, 23-C, 31-C, 45-C, 53-C, 67-C, 75-C).
MALDI-TOF, m/z¼1791.0 [MþNa]þ, 1808.2 [MþK]þ.
C100H120O28 requires: C, 67.86; H, 6.83%; found: C, 67.93;
H, 6.98%.
4.3. General procedure for the synthesis of 5-11
Spirane 3 or 4 (5.4 mmol) and 27 mmol Cs2CO3 in 0.9 l
acetonitrile were refluxed for 2 h. To the obtained suspen-
sion, under refluxing solvent, 5.4 mmol of ditosylated
polyethyleneglycol dissolved in 0.1 l acetonitrile were
added during 4 days using a syringe pump. The reflux of
the solvent was continued for one more day. The system was
brought to rt and the solid phase removed by filtration. The
acetonitrile was evaporated and the crude product was
dissolved in 300 ml CH2Cl2 and then washed with
2£100 ml solution of KOH 2% and 2£100 ml of water.
After drying (Na2SO4), the solvent was removed and the
crude product was subjected to flash chromatography.
4.3.1. 13,19,35,41-Tetramethyl-2,5,8,14,18,24,27,30,
36,40,47,50,55,58-tetradecaoxanonacyclo[40.2.29,12
.
2
13,16.216,19.220,23.231,34.235,38.238,41.21,42]hexaconta-9,
11,20,22,31,33,42,44(1),45,49,53,59-dodecaene (5b). Col-
orless solid, mixture of like and unlike isomers, mp 273–
275 8C, column chromatography, (ethylacetate/dichloro-
methane/heptane/methanol¼5/20/7.5/0.3; Rf¼0.25) 24.0%
yield. dH (600 MHz; CDCl3) 1.48, 1.50 (s, 12H, 13-CH3,
19-CH3, 35-CH3, 41-CH3), 3.07 (dd, J¼11.7, 2.0 Hz, 4H,
15-Heq, 17-Heq, 37-Heq, 39-Heq), 3.15, 3.17 (d, J¼11.7 Hz,
4H, 15-Hax, 17-Hax, 37-Hax, 39-Hax), 3.63, 3.64 (d, J¼
11.5 Hz, 4H, 48-Hax, 49-Hax, 56-Hax, 57-Hax), 3.89–3.97
(overlapped peaks, 8H, 4-H2, 6-H2, 26-H2, 28-H2), 4.14–
4.21 (overlapped peaks, 8H, 3-H2, 7-H2, 25-H2, 29-H2), 4.41
(d, J¼11.5 Hz, 4H, 48-Heq, 49-Heq, 56-Heq, 57-Heq), 6.91,
6.94 (d, J¼8.6 Hz, 8H, 10-H, 22-H, 32-H, 44-H, 45-H, 52-
H, 53-H, 60-H), 7.25, 7.28 (d, J¼8.6 Hz, 8H, 11-H, 21-H,
33-H, 43-H, 46-H, 51-H, 54-H, 59-H); dC (150 MHz;
CDCl3) 31.90 (13-CH3, 19-CH3, 35-CH3, 41-CH3), 32.29,
32.36 (16-C, 38-C), 64.72 (15-C, 17-C, 37-C, 39-C), 65.26
(48-C, 49-C, 56-C, 57-C), 68.19, 68.26 (3-C, 7-C, 25-C,
29-C), 70.30, 70.38 (4-C, 6-C, 26-C, 28-C), 101.09 (13-C,
19-C, 35-C, 41-C), 115.23, 115.29 (10-C, 22-C, 32-C, 44-C,
45-C, 52-C, 53-C, 60-C), 128.07, 128.13 (11-C, 21-C, 33-C,
43-C, 46-C, 51-C, 54-C, 59-C), 132.55, 132.61 (12-C, 20-C,
34-C, 42-C), 158.77 (1-C, 9-C, 23-C, 31-C). MALDI-TOF,
m/z¼885.3 [MþH]þ, 907.5 [MþNa]þ, 923.5 [MþK]þ.
C50H60O14 requires: C, 67.86; H, 6.83%; found: C, 67.97;
H, 6.76%.
4.3.3. 16,22,41,47-Tetramethyl-2,5,8,11,17,21,27,30,33,
36,42,46,53,56,61,64-hexadecaoxanonacyclo[46.2.212,15
.
2
16,19.219,22.223,26.237,40.241,44.244,47.21,48]hexahexaconta-
12,14,23,25,37,39,48,50(1),51,57,59,65-tetradecaene (6b).
Colorless solid, mixture of like and unlike isomers, mp
149–150 8C, column chromatography, (ethylacetate/hep-
tane¼3/2; Rf¼0.24) 34.0% yield. dH (600 MHz; CDCl3)
1.47, 1.48 (s, 12H, 16-CH3, 22-CH3, 41-CH3, 47-CH3),
3.09, 3.12 (dd, J¼11.7, 2.2 Hz, 4H, 18-Heq, 20-Heq, 43-Heq,
45-Heq), 3.19, 3.22 (d, J¼11.7 Hz, 4H, 18-Hax, 20-Hax,
43-Hax, 45-Hax), 3.57, 3.61 (d, J¼11.6 Hz, 4H, 54-Hax,
55-Hax, 62-Hax, 63-Hax), 3.76 (s, 8H, 6-H2, 7-H2, 31-H2,
32-H2), 3.87–3.89 (overlapped peaks, 8H, 4-H2, 9-H2, 29-
H2, 34-H2], 4.11–4.16 (overlapped peaks, 8H, 3-H2, 10-H2,
28-H2, 35-H2), 4.40, 4.42 (dd, J¼11.6, 2.2 Hz, 4H, 54-Heq,
55-Heq, 62-Heq, 63-Heq), 6.91, 6.92 (d, J¼8.8 Hz, 8H, 13-H,
25-H, 38-H, 50-H, 51-H, 58-H, 59-H, 66-H), 7.275, 7.278
(d, J¼8.8 Hz, 8H, 14-H, 24-H, 39-H, 49-H, 52-H, 57-H,
60-H, 65-H); dC (150 MHz; CDCl3) 31.88, 31.99 (16-CH3,
22-CH3, 41-CH3, 47-CH3), 32.27, 32.32 (19-C, 44-C), 64.80
(18-C, 20-C, 43-C, 45-C), 65.16 (54-C, 55-C, 62-C, 63-C),
67.68 (3-C, 10-C, 28-C, 35-C), 69.93 (4-C, 9-C, 29-C,
34-C), 71.17 (6-C, 7-C, 31-C, 32-C), 101.09 (16-C, 22-C,
41-C, 47-C), 114.94 (13-C, 25-C, 38-C, 50-C, 51-C, 58-C,
59-C, 66-C), 128.10 (14-C, 24-C, 39-C, 49-C, 52-C, 57-C,
60-C, 65-C), 132.46, 132.50 (15-C, 23-C, 40-C, 48-C),
4.3.2. 13,19,35,41,57,63,79,85-Octamethyl-2,5,8,14,18,
24,27,30,36,40,46,49,52,58,62,68,71,74,80,84,91,94,99,10-
2,107,110,115,118-octacosaoxaheptadecacyclo[84.2.
2
2
9,12.213,16.216,19.220,23.231,34.235,38.238,41.242,45.253,56
.
57,60.260,63.264,67.275,78.279,82.282,85.21,86]cosacenta-
9,11,20,22,31,33,42,44,53,55,64,66,75,77,86,88(1),89,95,

M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
4797
158.61 (1-C, 12-C, 26-C, 37-C). FAB, m/z¼973.5 [MþH]þ.
C54H68O16 requires: C, 66.65; H, 7.04%; found: C, 66.46;
H, 7.18%.
J¼11.7 Hz, 2H, 24-Hax, 26-Hax), 3.15–3.26 (overlapped
peaks, 8H, 6-H2, 7-H2, 12-H2, 13-H2), 3.26 [ddd, J¼13.9,
5.5, 2.6 Hz, 2H, 4-H(H0), 15-H(H0)], 3.31 (s, 4H, 9-H2,
10-H2), 3.33 [ddd, J¼13.9, 6.6, 2.7 Hz, 2H, 4-H(H0),
15-H(H00)], 3.78 [ddd, J¼12.4, 5.5, 2.7 Hz, 2H, 3-H(H0),
16-H(H )], 3.89 (d, J¼11.2 Hz, 2H, 35-Hax, 36-Hax), 3.96
[ddd, J¼12.4, 6.6, 2.6 Hz, 2H, 3-H(H0), 16-H(H0)], 4.00 (d,
J¼11.2 Hz, 2H, 35-Heq, 36-Heq), 6.97 (d, J¼8.6 Hz, 4H,
19-H, 31-H, 32-H, 39-H), 7.35 (d, J¼8.6 Hz, 4H, 20-H,
30-H, 33-H, 38-H); dC (150 MHz; C6D6) 31.01 (22-CH3,
28-CH3), 34.91 (25-C), 64.54 (24-C, 26-C), 65.88 (35-C,
36-C), 68.44 (3-C, 16-C), 71.13 (9-C, 10-C), 71.23, 71.27
(6-C, 7-C, 12-C, 13-C), 71.49 (4-C, 15-C), 101.64 (22-C,
28-C), 116.51 (19-C, 31-C, 32-C, 39-C), 128.61 (20-C,
30-C, 33-C, 38-C), 134.36 (21-C, 29-C), 159.74 (1-C,
18-C); MS (CI, 150 eV): m/z¼575 [MþH]þ. C31H42O10
requires: C, 64.79; H, 7.37%; found: C, 64.66; H, 7.51%.
4.3.4. 19,25-Dimethyl-2,5,8,11,14,20,24,31,34-nona-oxa-
pentacyclo[24.2.215,18.219,22.222,25. 21,26]hexatriaconta-
15,17,26,28(1),29,35-hexaene (7a). Colorless oil, column
chromatography, (chloroform/ethylacetate/heptane/metha-
nol¼4/1/5/0.1; Rf¼0.28) 6.0% yield. dH (500 MHz; C6D6)
1.64 (s, 6H, 19-CH3, 25-CH3), 2.63 (d, J¼11.5 Hz, 2H,
21-Heq, 23-Heq), 3.34 (d, J¼11.5 Hz, 2H, 21-Hax, 23-Hax),
3.15–3.37 (overlapped peaks, 12H, 4-H2, 6-H2, 7-H2, 9-H2
10-H2, 12-H2), 3.66 (d, J¼11.0 Hz, 2H, 32-Hax, 33-Hax),
3.77 [ddd, J¼13.0, 5.5, 3.0 Hz, 2H, 3-H(H0), 13-H(H0)], 3.90
(d, J¼11.0 Hz, 2H, 32-Heq, 33-Heq), 3.93 [ddd, J¼13.0, 6.5,
3.0 Hz, 2H, 3-H(H0), 13-H(H0)], 6.92 (d, J¼9.0 Hz, 4H,
16-H, 28-H, 29-H, 36-H), 7.36 (d, J¼9.0 Hz, 4H, 17-H,
27-H, 30-H, 35-H); dC (125 MHz; C6D6) 30.66 (19-CH3,
25-CH3), 36.46 (22-C), 64.58 (21-C, 23-C), 65.28 (32-C,
33-C), 68.32 (3-C, 13-C), 70.94, 71.17, 71.42 (4-C, 6-C,
7-C, 9-C, 10-C, 12-C), 101.54 (19-C, 25-C), 116.55 (16-C,
28-C, 29-C, 36-C), 135.02 (18-C, 26-C), 159.70 (1-C,
15-C), MS (EI, 70 eV): m/z¼530 [M]þ. C29H38O9 requires:
C, 65.64; H, 7.22%; found: C, 65.82; H, 7.03%.
4.3.7. 22,28,53,59-Tetramethyl-2,5,8,11,14,17,23,27,33,
36,39,42,45,48,54,58,65,68,73,76-cosaoxanonacyclo-
[58.2.218,21.222,25.225,28.229,32.249,52.253,56.256,59.21,60]octa-
heptaconta-18,20,29,31,49,51,60,62(1),63,69,71,77-
dodecaene (8b). Colorless solid, mixture of like and unlike
isomers, mp 148–149 8C, column chromatography, (ethyl-
acetate/dichloromethane/petroleum ether/methanol¼10/5/
3/0.2; Rf¼0.10) 22.0% yield. dH (600 MHz; C6D6) 1.64,
1.65 (s, 12H, 22-CH3, 28-CH3, 53-CH3, 59-CH3), 2.91 (d,
J¼11.4 Hz, 4H, 24-Heq, 26-Heq, 55-Heq, 57-Heq), 3.172,
3.178 (d, J¼11.4 Hz, 4H, 24-Hax, 26-Hax, 55-Hax, 57-Hax),
3.452, 3.454 (s, 24H, 6-H2, 7-H2, 9-H2, 10-H2, 12-H2,
13-H2, 37-H2, 38-H2, 40-H2, 41-H2, 43-H2, 44-H2), 3.54–
3.57 (overlapped peaks, 8H, 4-H2, 15-H2, 35-H2, 46-H2),
3.71 (d, J¼11.4 Hz, 4H, 66-Hax, 67-Hax, 74-Hax, 75-Hax),
3.801–3.816 (overlapped peaks, 8H, 3-H2, 16-H2, 34-H2,
47-H2), 4.71 (d, J¼11.4 Hz, 4H, 66-Heq, 67-Heq, 74-Heq,
75-Heq), 6.87, 6.88 (d, J¼8.6 Hz, 8H, 19-H, 31-H, 50-H,
62-H, 63-H, 70-H, 71-H, 78-H), 7.34, 7.35 (d, J¼8.6 Hz,
8H, 20-H, 30-H, 51-H, 61-H, 64-H, 69-H, 72-H, 77-H); dC
(75 MHz; C6D6) 32.99 (22-CH3, 28-CH3, 53-CH3, 59-CH3),
33.02 (25-C, 56-C), 65.37 (24-C, 26-C, 55-C, 57-C), 65.91
(66-C, 67-C, 74-C, 75-C), 68.30 (3-C, 16-C, 34-C, 47-C),
70.48 (9-C, 10-C, 40-C, 41-C), 71.67 (6-C, 7-C, 12-C, 13-C,
37-C, 38-C, 43-C, 44-C), 71.77 (4-C, 15-C, 35-C, 46-C),
101.86 (22-C, 28-C, 53-C, 59-C), 115.74 (19-C, 31-C, 50-C,
62-C, 63-C, 70-C, 71-C, 78-C), 133.58 (21-C, 29-C, 52-C,
60-C), 159.69 (1-C, 18-C, 32-C, 49-C); MALDI-TOF, m/z¼
1171.1 [MþNa]þ, 1187.0 [MþK]þ. C62H84O20 requires: C,
64.79; H, 7.37%; found: C, 64.68; H, 7.21%.
4.3.5. 19,25,47,53-Tetramethyl-2,5,8,11,14,20,24,30,
33,36,39,42,48,52,59,62,67,70-octadecaoxanonacyclo-
[52.2.215,18.219,22.222,25.226,29.243,46.247,50.250,53.21,54]do-
heptaconta-15,17,26,28,43,45,54,56(1),57,63,65,71-
dodecaene (7b). Colorless solid, mixture of like and unlike
isomers, mp 175–177 8C, column chromatography, (chloro-
form/ethylacetate/heptane/methanol¼4/1/5/0.1; Rf¼0.16)
18.0% yield. dH (600 MHz; C6D6) 1.63, 1.64 (s, 12H,
19-CH3, 25-CH3, 47-CH3, 53-CH3), 2.92–2.94 (overlapped
peaks, 4H, 21-Heq, 23-Heq, 49-Heq, 51-Heq), 3.17, 3.18 (d,
J¼12.0 Hz, 4H, 21-Hax, 23-Hax, 49-Hax, 51-Hax), 3.45 (s,
16H, 6-H2, 7-H2, 9-H2, 10-H2, 34-H2, 35-H2, 37-H2, 38-H2),
3.55–3.58 (overlapped peaks, 8H, 4-H2, 12-H2, 32-H2,
40-H2], 3.70, 3.71 (d, J¼11.4 Hz, 4H, 60-Hax, 61-Hax,
68-Hax, 69-Hax), 3.80–3.81 (overlapped peaks, 8H, 3-H2,
13-H2, 31-H2, 41-H2), 4.68, 4.70 (d, J¼11.4 Hz, 4H, 60-Heq,
61-Heq, 68-Heq, 69-Heq), 6.87 (d, J¼8.0 Hz, 8H, 16-H,
28-H, 44-H, 56-H, 57-H, 64-H, 65-H, 72-H), 7.34, 7.35 (d,
J¼8.0 Hz, 8H, 17-H, 27-H, 45-H, 55-H, 58-H, 63-H, 66-H,
71-H); dC (75 MHz; C6D6) 32.99 (22-C, 50-C), 33.05
(19-CH3, 25-CH3, 47-CH3, 53-CH3), 65.37 (21-C, 23-C,
49-C, 51-C), 65.89 (60-C, 61-C, 68-C, 69-C), 68.29 (3-C,
13-C, 31-C, 41-C), 70.49 (4-C, 12-C, 32-C, 40-C), 71.71,
71.76, 71.79 (6-C, 7-C, 9-C, 10-C, 34-C, 35-C, 37-C, 38-C),
101.85 (19-C, 25-C, 47-C, 53-C), 115.75 (16-C, 28-C, 44-C,
56-C, 57-C, 64-C, 65-C, 72-C), 133.58 (18-C, 26-C, 46-C,
54-C) 159.68 (1-C, 15-C, 29-C, 43-C); MALDI-TOF,
m/z¼1061.2 [MþH]þ, 1083.7 [MþNa]þ, 1100.2 [MþK]þ.
C58H76O18 requires: C, 65.64; H, 7.22%; found: C, 65.49;
H, 7.08%.
4.3.8. 25,31-Dimethyl-2,5,8,11,14,17,20,26,30,37,40-
undeca-oxapentacyclo[30.2.221,24.225,28.228,31.21,32]do-
tetraconta-21,23,32,34(1),35,41-hexaene (9a). Colorless
solid, mp 97–98 8C, column chromatography, (dichloro-
methane/methanol¼32/1; Rf¼0.33) 17.0% yield. dH
(600 MHz; C6D6) 1.66 (s, 6H, 25-CH3, 31-CH3), 3.01 (d,
J¼11.7 Hz, 2H, 27-Heq, 29-Heq), 3.07 (d, J¼11.7 Hz, 2H,
27-Hax, 29-Hax), 3.21–3.39 (overlapped peaks, 20H, 4-H2,
6-H2, 7-H2, 9-H2, 10-H2, 12-H2, 13-H2, 15-H2, 16-H2, 18-
H2), 3.81 [ddd, J¼12.3, 5.5, 2.6 Hz, 2H, 3-H(H0), 19-H(H0)],
3.85 (d, J¼11.4 Hz, 2H, 38-Hax, 39-Hax), 3.95 [ddd, J¼
12.3, 6.6, 2.4 Hz, 2H, 3-H(H0), 19-H(H0)], 4.31 (d, J¼
11.4 Hz, 2H, 38-Heq, 39-Heq), 7.01 (d, J¼8.7 Hz, 4H, 22-H,
34-H, 35-H, 42-H), 7.36 (d, J¼8.7 Hz, 4H, 23-H, 33-H,
4.3.6. 22,28-Dimethyl-2,5,8,11,14,17,23,27,34,37-deca-
oxa-pentacyclo[27.2.218,21.222,25.225,28.21,29]nonatria-
conta-18,20,29,31(1),32,38-hexaene (8a). Colorless solid,
mp 118 8C, column chromatography, (ethylacetate/dichloro-
methane/petroleum ether/methanol¼10/5/3/0.2; Rf¼0.40)
20.0% yield. dH (600 MHz; C6D6) 1.65 (s, 6H, 22-CH3,
28-CH3), 2.77 (d, J¼11.7 Hz, 2H, 24-Heq, 26-Heq), 3.13 (d,

4798
M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
36-H, 41-H); dC (150 MHz; C6D6) 31.64 (25-CH3, 31-CH3),
33.89 (28-C), 64.89 (27-C, 29-C), 66.10 (38-C, 39-C), 68.62
(3-C, 19-C), 71.28, 71.33, 71.36, 71.43, 71.54 (4-C, 6-C,
7-C, 9-C, 10-C, 12-C, 13-C, 15-C, 16-C, 18-C), 101.74
(25-C, 31-C), 116.58 (22-C, 34-C, 35-C, 42-C), 128.91
(23-C, 33-C, 36-C, 41-C), 133.96 (24-C, 32-C), 159.82
(1-C, 21-C); MS (CI, 150 eV): m/z¼619 [MþH]þ.
C33H46O11 requires: C, 64.06; H, 7.49%; found: C, 63.88;
H, 7.66%.
38-CH3, 44-CH3), 32.24 (17-C, 41-C), 65.02 (16-C, 18-C,
40-C, 42-C), 65.34 (51-C, 52-C, 57-C, 58-C), 67.71 (3-C,
7-C, 27-C, 31-C), 70.27 (4-C, 6-C, 28-C, 30-C), 101.15
(14-C, 20-C, 38-C, 44-C), 112.95 (49-C, 54-C, 55-C, 60-C),
114.21 (10-C, 24-C, 34-C, 48-C), 119.49 (12-C, 22-C, 36-C,
46-C), 130.07 (11-C, 23-C, 35-C, 47-C), 142.24 (13-C,
21-C, 37-C, 45-C), 159.54 (9-C, 25-C, 33-C, 1-C); MALDI-
TOF, m/z¼885.0 (Mþ1), 907.5 [MþNa]þ, 923.4 [MþK]þ.
C50H60O14 requires: C, 67.86; H, 6.83%; found: C, 67.92;
H, 6.90%.
4.3.9. 25,31,59,65-Tetramethyl-2,5,8,11,14,17,20,26,30,
36,39,42,45,48,51,54,60,64,71,74,79,82-docosaoxa-nona-
cyclo[64.2.221,24.225,28.228,31.232,35.255,58.259,62.262,65.21,66]-
tetraoctaconta-21,23,32,34,55,57,66,68(1),69,75,77,83-
dodecaene (9b). Colorless oil, mixture of like and unlike
isomers, column chromatography, (dichloromethane/metha-
nol¼32/1; Rf¼0.22) 15.0% yield. dH (600 MHz; CDCl3)
1.46, 1.47 (s, 12H, 25-CH3, 31-CH3, 59-CH3, 65-CH3), 3.11
(d, J¼11.4 Hz, 4H, 27-Heq, 29-Heq, 61-Heq, 63-Heq), 3.22
(d, J¼11.4 Hz, 4H, 27-Hax, 29-Hax, 61-Hax, 63-Hax), 3.60
(d, J¼11.4 Hz, 4H, 72-Hax, 73-Hax, 80-Hax, 81-Hax), 3.65–
3.73 (overlapped peaks, 32H, 6-H2, 7-H2, 9-H2, 10-H2,
12-H2, 13-H2, 15-H2, 16-H2, 40-H2, 41-H2, 43-H2, 44-H2,
46-H2, 47-H2, 49-H2, 50-H2), 3.85–3.86 (overlapped peaks,
8H, 4-H2, 18-H2, 38-H2, 52-H2), 4.12–4.14 (overlapped
peaks, 8H, 3-H2, 19-H2, 37-H2, 53-H2), 4.41 (d, J¼11.4 Hz,
4H, 72-Heq, 73-Heq, 80-Heq, 81-Heq), 6.91, 6.92 (d, J¼
8.8 Hz, 8H, 22-H, 34-H, 56-H, 68-H, 69-H, 76-H, 77-H,
84-H), 7.29, 7.30 (d, J¼8.8 Hz, 8H, 23-H, 33-H, 57-H,
67-H, 70-H, 75-H, 78-H, 83-H); dC (150 MHz; CDCl3)
32.01 (25-CH3, 31-CH3, 59-CH3, 65-CH3), 32.39 (28-C,
62-C), 64.83 (27-C, 29-C, 61-C, 63-C), 65.15 (72-C, 73-C,
80-C, 81-C), 67.65 (3-C, 19-C, 37-C, 53-C), 69.92 (4-C,
18-C, 38-C, 52-C), 70.77, 70.84, 70.90, 71.09 (6-C, 7-C,
9-C, 10-C, 12-C, 13-C, 15-C, 16-C, 40-C, 41-C, 43-C, 44-C,
46-C, 47-C, 49-C, 50-C), 101.11 (25-C, 31-C, 59-C, 65-C),
114.93 (22-C, 34-C, 56-C, 68-C, 69-C, 76-C, 77-C, 84-C),
128.16 (23-C, 33-C, 57-C, 67-C, 70-C, 75-C, 78-C, 83-C),
132.50 (24-C, 32-C, 58-C, 66-C), 158.61 (1-C, 21-C, 35-C,
55-C); MALDI-TOF, m/z¼1237.4 [MþH]þ, 1259.6
[MþNa]þ, 1275.7 [MþK]þ. C66H92O22 requires: C,
64.06; H, 7.49%; found: C, 64.21; H, 7.54%.
4.3.11. 17,23-Dimethyl-2,5,8,11,18,22,29,32-octaoxa-
penta-cyclo[22.3.217,20.220,23.11,24.112,16]tritriaconta-
1(33),12,14,16(28),24,26-hexaene (11a). Colorless oil,
column chromatography, (ethylacetate/heptane¼2/3; Rf¼
0.35) 15.0% yield. dH (600 MHz; C6D6) 1.63 (s, 6H,
17-CH3, 23-CH3), 3.11 (d, J¼11.5 Hz, 2H, 19-Heq, 21-Heq),
3.31–3.38 [overlapped peaks, 6H, 4-H(H0), 9-H(H0)], 6-H2,
7-H2), 3.44 [ddd, J¼10.8, 6.0, 4.8 Hz, 2H, 4-H(H0),
9-H(H0)], 3.64 (d, J¼11.5 Hz, 2H, 19-Hax, 21-Hax), 3.68
(d, J¼11.3 Hz, 2H, 30-Hax, 31-Hax), 3.87 (d, J¼11.3 Hz,
2H, 30-Heq, 31-Heq), 3.95 [ddd, J¼12.0, 5.4, 4.8 Hz, 2H,
3-H(H00), 10-H(H00)], 4.01 [ddd, J¼12.0, 6.0, 4.8 Hz, 2H,
3-H(H ), 10-H(H )], 6.91 (ddd, J¼8.0, 2.4, 1.2 Hz, 2H,
13-H, 27-H), 7.03 [dt (overlapped ddd), J¼8.0, 1.5, 1.2 Hz,
2H, 15-H, 25-H]; 7.10 [t (overlapped dd), J¼8.0 Hz, 2H,
14-H, 26-H]; 7.58 (dd, J¼2.4, 1.2 Hz, 2H, 28-H, 33-H]; dC
(150 MHz; C6D6) 28.48 (17-CH3, 23-CH3), 35.15 (20-C),
65.03 (19-C, 21-C), 65.95 (30-C, 31-C), 68.47 (3-C, 10-C),
70.70 (4-C, 9-C), 71.10 (6-C, 7-C), 101.31 (17-C, 23-C),
113.66 (28-C, 33-C), 117.78 (13-C, 27-C), 119.89 (15-C,
25-C), 130.39 (14-C, 26-C), 144.37 (16-C, 24-C), 160.36
(1-C, 12-C); MS (EI, 70 eV): m/z¼486 [M]þ.C27H34O8
requires: C, 66.65; H, 7.04%; found: C, 66.59; H, 7.18%.
4.3.12. 17,23,44,50-Tetramethyl-2,5,8,11,18,22,29,32,35,
38,45,49,56,59,62,65-hexadecaoxanona cyclo[49.3.217,20
.
2
20,23.244,47.247,50.11,51.112,16.124,28.139,43]hexa hexaconta-
1(66),12,14,16(55),24,26,28(60),39,41,43(61),51,53-do-
decaene (11b). Colorless solid, mixture of like and unlike
isomers, mp 139–140 8C, column chromatography, (ethyl-
acetate/heptane¼2/3; Rf¼0.11) 17.0% yield. dH (500 MHz;
CDCl3) 1.44, 1.45 (s, 12H, 17-CH3, 23-CH3, 44-CH3,
50-CH3), 3.07 (d, J¼11.5 Hz, 4H, 19-Heq, 21-Heq, 46-Heq,
48-Heq), 3.22 (d, J¼11.5 Hz, 4H, 19-Hax, 21-Hax, 46-Hax,
48-Hax), 3.60 (d, J¼11.5 Hz, 4H, 57-Hax, 58-Hax, 63-Hax,
64-Hax), 3.74 (s, 8H, 6-H2, 7-H2, 33-H2, 34-H2), 3.84–3.86
(overlapped peaks, 8H, 4-H2, 9-H2, 31-H2, 36-H2), 4.08–
4.11 (overlapped peaks, 8H, 3-H2, 10-H2, 30-H2, 37-H2),
4.41 (d, J¼11.5 Hz, 4H, 57-Heq, 58-Heq, 63-Heq, 64-Heq),
6.82, 6.83 [dt (overlapped ddd), 4H, 13-H, 27-H, 40-H,
54-H), 6.93–6.99 (overlapped peaks, 8H, 15-H, 25-H, 42-H,
52-H, 55-H, 60-H, 61-H, 66-H), 7.25 (t, J¼7.5 Hz, 4H,
14-H, 26-H, 41-H, 53-H); dC (125 MHz; CDCl3) 31.90
(17-CH3, 23-CH3, 44-CH3, 50-CH3), 32.27 (20-C, 47-C),
65.00 (19-C, 21-C, 46-C, 48-C), 65.31 (57-C, 58-C, 63-C,
64-C), 67.67 (3-C, 10-C, 30-C, 37-C), 70.04 (4-C, 9-C,
31-C, 36-C), 71.11, 71.19 (6-C, 7-C, 33-C, 34-C), 101.13
(17-C, 23-C, 44-C, 50-C), 113.13 (55C, 60-C, 61-C, 66-C),
114.18 (13-C, 27-C, 40-C, 54-C), 119.37 (15-C, 25-C, 42-C,
52-C), 130.03 (14-C, 26-C, 41-C, 53-C), 142.25 (16-C,
24-C, 43-C, 51-C), 159.57 (1-C, 12-C, 28-C, 39-C);
MALDI-TOF, m/z¼995.2 [MþNa]þ, 1011.2 [MþK]þ.
4.3.10. 14,20,38,44-Tetramethyl-2,5,8,15,19,26,29,32,
39,43,50,53,56,59-tetradecaoxanonacyclo[43.3.214,17
.
2
17,20.238,41.241,44.11,45.19,13.121,25.133,37]hexaconta-
1(60),9,11,13(49),21,23,25(54),33,35,37(55),45,47-do-
decaene (10b). Colorless solid, mixture of like and unlike
isomers, mp 126–128 8C, column chromatography, (ethyl-
acetate/dichloromethane/heptane¼1/4/2; Rf¼0.13) 27.0%
yield dH (500 MHz; CDCl3) 1.45 (s, 12H, 14-CH3,
20-CH3, 38-CH3, 44-CH3), 3.05 (dd, J¼12.0, 2.0 Hz, 4H,
16-Heq, 18-Heq, 40-Heq, 42-Heq), 3.19 (d, J¼12.0 Hz, 4H,
16-Hax, 18-Hax, 40-Hax, 42-Hax), 3.62 (d, J¼11.5 Hz, 4H,
51-Hax, 52-Hax, 57-Hax, 58-Hax), 3.90–3.93 (overlapped
peaks, 8H, 4-H2, 6-H2, 28-H2, 30-H2), 4.12–4.14 (t, J¼
4.8 Hz, 8H, 3-H2, 7-H2, 27-H2, 31-H2], 4.41 (dd, J¼11.5,
2.0 Hz, 4H, 51-Heq, 52-Heq, 57-Heq, 58-Heq), 6.83, 6.84 [dt
(overlapped ddd), J¼8.0, 2.0 Hz, 4H, 10-H, 24-H, 34-H,
48-H], 6.91–6.92 (overlapped peaks, 4H, 49-H, 54-H, 55-H,
60-H); 7.00 [dt (overlapped ddd), J¼8.0, 2.0 Hz, 4H, 12-H,
22-H, 36-H, 46-H]; 7.28 (t, J 8.0 Hz, 4H, 11-H, 23-H, 35-H,
47-H); dC (125 MHz; CDCl3) 32.00 (14-CH3, 20-CH3,

M. Balog et al. / Tetrahedron 60 (2004) 4789–4799
4799
14. Garcia, C.; Guyot, J.; Jeminet, G.; Leize-Wagner, E.;
Nierengarten, H.; Van Dorsselaer, A. Tetrahedron Lett.
1999, 40, 4997–5000.
C54H68O16 requires: C, 66.65; H, 7.04%; found: C, 66.83;
H, 6.92%.
15. Abramson, S.; Ashkenasi, E.; Goldemberg, I.; Greenwald, M.;
Jatzke, H.; Vardi, M.; Weinman, S.; Fuchs, B. J. Chem. Soc,
Chem. Commun. 1994, 1611–1612.
Acknowledgements
The Region of Haute-Normandie and AUF (Agence
Universitaire de la Francophonie, PAS26/2001) are grate-
fully acknowledged for the fellowships given to Mirela
Balog and CNCSIS and PNCDI are acknowledged for the
financial support (grants A1736/2003 and CERES 3-109) of
this work.
16. Senderowitz, H.; Linden, A.; Goldender, L.; Abramson, S.;
Fuchs, B. Tetrahedron 1994, 50, 9691–9706.
17. Senderowitz, H.; Goldender, L.; Fuchs, B. Tetrahedron 1994,
50, 9707–9728.
18. Jatzke, H.; Frische, K.; Greenwald, M.; Golender, L.; Fuchs,
B. Tetrahedron 1997, 53, 4821–4834.
´
´
´
19. Bako, P.; Novak, T.; Ludanyi, K.; Pete, B.; To˜ke, L.;
Keglevich, G. Tetrahedron: Asymmetry 1999, 10, 2373–2380.
20. Galan, M. C.; Venot, A. P.; Glushka, J.; Imberty, A.; Boons,
G. J. J. Am. Chem. Soc. 2002, 124, 5964–5973.
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