Synthesis and conformational analysis of macrocyclic dihydroxystilbenes linked between the para-para positions

Article abstract of DOI:10.1002/chem.200700323

A new family of diphenylethanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. The two phenyl rings are linked between the para-phenolic positions through a 3-oxapentamethylene or hexamethylene chain. The key

Full text of DOI:10.1002/chem.200700323

DOI: 10.1002/chem.200700323
Synthesis and Conformational Analysis of Macrocyclic Dihydroxystilbenes
Linked between the para–para Positions
A
Carmen Mateo, Vilmarí López, Manuel Medarde,* and Rafael Pelµez*[a]
Abstract: A new family of diphenyl-
ethanes has been synthesized as confor-
mationally restricted analogues of anti-
mitotic combretastatins. The two
phenyl rings are linked between the
para-phenolic positions through a 3-ox-
apentamethylene or hexamethylene
chain. The key macrocyclization step
was achieved in moderate yields by
using an intramolecular McMurry pina-
col coupling of linked aromatic dialde-
hydes, except for the nitro-substituted
compounds. The relative stereochemis-
try of the isomeric pinacols was deter-
mined by a combination of spectro-
scopic, chemical derivatization, and
molecular-modeling approaches. The
NMR spectra of these compounds
(with a polyoxygenated crownophane
skeleton) indicate severe conformation-
al restrictions relative to their parent
combretastatins; the rotation of the
phenyl rings is hampered by interac-
tions of their substituents and the
linker and the conformational restric-
tions imposed by the substituted
bridge.
Keywords: combretastatin
ana-
logues · conformational analysis ·
cyclophanes · macrocycles
Introduction
ities through inhibition of microtubule polymerization by in-
teraction at the colchicine site of tubulin.[7] Since their initial
discovery in the early 1980s by Pettit et al.,[8] many struc-
ture–activity relationship (SAR) studies have been directed
at the elucidation of the structural requirements for such
small molecules to be cytotoxic. These SAR studies investi-
gated the influence of the structure and substituents on the
A,B rings and/or the structure of the bridge between them
and showed that 3,4,5-trimethoxy- and 4-methoxy-3-X-sub-
stituted phenyl systems (X=H, OH, NH2, and their amino
acid, phosphate, or other derivatives for solubilizing purpos-
es) in a close non-coplanar disposition and separated by 0–
4-atom bridges are the common structural features of the
active compounds.[9] These results are often summarized on
the two-atom bridged structure of combretastatin A-4
(Scheme 1), one of the most potent inhibitors of tubulin
polymerization, and colchicine binding to tubulin, which
also shows highly potent cytotoxic and antiangiogenic activi-
ties.
Conformational restriction of freely rotating moieties is a
way to modify the properties of molecules, as is the case in
the discovery and optimization of biological activities.[1] This
approach, based on the benefit produced by the entropic
factor derived from the absence of the required freezing of
conformational freedom upon binding, has been applied to
the investigation of different types of pharmacologically
active families, for example, anticancer taxoids,[2] peptides,[3]
and g-aminobutyric acid (GABA) analogues[4] or histamine
analogues.[5]
Combretastatins are very interesting diphenylethanoids of
natural origin that have been thoroughly studied as a result
of their high cytotoxic and antiangiogenic activities and
their simple structures.[6] These compounds exert these activ-
In stilbenes, there is a low energetic barrier to the rotation
of the phenyl rings,[10] but in combretastatins only the effects
of the relative distance between the rings, coplanarity, and
chirality on their biological activity have been investigated
by the synthesis of many analogues. Towards this end, phen-
anthrene analogues,[11] the isomeric dioxolane analogues of
CA-4,[12] and the isomeric pinacols derived from CA-4[13]
and CA-1[14] have been synthesized and assayed. The
S,S isomers showed stronger antitubulin activity and cyto-
[a] Dr. C. Mateo, V. López, Prof. M. Medarde, Dr. R. Pelµez
Laboratorio de Química Orgµnica y FarmacØutica
Facultad de Farmacia
Universidad de Salamanca
Campus Miguel de Unamuno, 37007 Salamanca (Spain)
Fax : (+34)923-294-515
E-mail: medarde@usal.es
pelaez@usal.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the authors.
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FULL PAPER
ucts and that recently the ef-
fects of macrocyclization and
stereochemistry (on both the
precursors and the macro rings
themselves) on the perfor-
mance of small molecules in
biological assays have been
demonstrated,[16] we decided to
investigate the effect of macro-
cyclization on the activity of
several antimitotic agents. Ac-
cordingly, during our study di-
Scheme 1. General structure of combretastatins and related colchicine site ligands and the structures of rele-
vant combretastatins.
toxic activity towards multidrug-resistant (MDR) cells
(Scheme 2).
rected at the synthesis and evaluation of new cytotoxic
agents based on natural products,[17] we designed several stil-
benophanes[18] and crowno-
phanes[19] as macrocyclic deriv-
atives of the antimitotic agents
combretastatin A-4 and relat-
ed compounds (Scheme 4).[20]
Related
paracyclophanes[21]
have found application in
supramolecular and materials
chemistry[22] and, although
much less frequently, as bio-
logically active compounds.[23]
The same design strategy was
Scheme 2. Combretastatin analogues with different degrees of conformational restriction.
Recently, the structures of two colchicine binding site li-
gands, podophyllotoxin and N-deacetyl-N-(2-mercaptoace-
tyl)colchicine (DAMA-colchicine), complexed with tubulin
have been disclosed.[15] The superposition of the bound li-
gands (Scheme 3) has shown that the protein adjusts to their
shapes and allows a different disposition of the aromatic
rings for the two ligands, in good agreement with the ob-
served tolerance of bridges of different lengths between the
two aromatic rings.
applied by Nelson and co-workers to bisindolemaleimides,
whose conformations are controlled by the size of the mac-
rocyclic ring in which they are constrained, thus allowing
them to chemically compare and discriminate the adenosine
5’-triphosphate (ATP) binding sites of protein kinases in the
absence of detailed structural information.[24]
Several possible macro ring sizes (depending on the linker
size and bonding position on each ring) are attainable with
the substitution pattern of the parent combretastatins for p–
p, p–m, and m–p macrocyclic rings (Scheme 4). Herein, we
disclose our results on the synthesis and the structural con-
sequences of the cyclization through the para positions of
Taking into consideration that conformational restriction
by macrocyclization has previously been intuited to enhance
binding affinity and metabolic stability of the resulting prod-
Scheme 3. Superimposition (center) and structures of DAMA-colchicine (left: ball and sticks in superimposition) and podophyllotoxin (right: thicker
wireframe in superimposition) in complex with tubulin.
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7247

R. Pelµez, M. Medarde et al.
Scheme 4. Design of macrocyclic analogues of combretastatins and examples of structural possibilities (p–p, p–m, and m–p indicate the relative disposi-
tion between the bridge and the spacer in the tetrasubstituted–trisubstituted rings).
DCA4 that leads to conformationally restricted paracyclo-
phane analogues of combretastatins.
instead to attempt a McMurry pinacol reaction of cross-
linked dialdehydes,[25] which could in turn be prepared from
commercially available phenolic aldehydes through two con-
secutive Mitsunobu reactions.[26] The same synthetic se-
quence was considered suitable to access macrocyclic ana-
logues of aminocombretastatin A-4 (ACA4) starting from
appropriate nitro derivatives.
The first substitution was carried out using a four- to ten-
fold excess of either diethylene glycol or 1,6-hexanediol and
the commercially available phenolic aldehydes under typical
Mitsunobu conditions, thus yielding aldehydes 1a–g
(Scheme 6). The water-soluble starting-material diols were
The designed compounds are polyoxygenated macrocycles
closed through a polymethylene or polyether chain that
share, in part, the structure of crownophanes. The para–para
macro-ring closure was selected in an attempt to modify by
as little as possible the substitution pattern of DCA-4 and
the superimposed models of CA-4, as it is taken into ac-
count that their calculated conformations are very close to
those adopted by colchicine and podophyllotoxin when com-
plexed with tubulin. The hexamethylene or the 3-oxapenta-
methylene linkers were selected as the smallest possible
spacers able to connect the
two para positions of the com-
bretastatins without affecting
bond angles and lengths. The
synthesis of these derivatives
and the study of their accessi-
ble conformations are of high
interest to rationalize the
effect that this modification
could produce on their biologi-
cal properties.
Scheme 6. Synthesis of the dialdehydes. Reagents and conditions (1 equiv=1 mol per mol): i) diethylene glycol
or 1,6-hexanediol (4–10 equiv), DBAD or DIAD (1.5–2.0 equiv), Ph3P resin (2equiv), CH 2Cl2 (dry), 48 h;
ii) 3-substituted-4-hydroxybenzaldehyde (1.2equiv), DBAD or DIAD (1.5–2.0 equiv), Ph 3P resin (2equiv), 48–
70 h (45–80% over two steps).
Results and Discussion
We planned the synthesis of
the title compounds as depict-
ed in Scheme 5. The formation
of the bisbenzylic bond was selected for the key macrocycli-
zation step for synthetic simplicity and versatility. Previous
attempts of a related synthesis made us discard a strategy
based upon ring-closing metathesis reactions.[20] We decided
readily removed during aqueous work-up. Once the diols
had been removed, the crude reaction products could be di-
rectly used in the second Mitsunobu reaction. The more
sterically hindered ortho-disubstituted phenolic aldehydes
were usually employed in the
first instance, but similar yields
were also achieved with the re-
verse order of the aldehydes.
After the two Mitsunobu reac-
tions, careful purification of di-
aldehydes 2a–f is mandatory,
as the reaction by-products in-
terfere with the McMurry reac-
tion. We finally decided to
employ polymer-bound triphe-
Scheme 5. Retrosynthetic analysis of the macrocyclic analogues of combretastatins.
nylphosphine in the Mitsunobu
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Conformational Behavior Study of Macrocycle Stilbenes
FULL PAPER
Table 1. Summary of McMurry pinacol reaction results.
reactions, which increased the reaction times somewhat, but
allowed ready removal of the reagent by filtration. The
other excess reactants (diisopropyl diazodicarboxylate
(DIAD) or di-tert-butylazodicarboxylate (DBAD)) or the
reduced by-products were also detrimental for the coupling
reactions, so we tried acid-labile derivatives in an attempt to
simplify purification. However, the 3-oxapentamethylene
bridge was unstable under the acidic conditions employed to
remove DBAD, and also the semicarbazide and/or hydra-
zine released from these reagents reacted with the dialde-
hydes. Subsequent attempts to hydrolyze the semicarba-
zones or hydrazones did not yield the expected results, and
we finally opted for a chromatographic purification of the
dialdehydes before the McMurry reactions.
Dialdehyde Reagent [molmolÀ1
]
Product
Yield [%][a]
)
2a
C
3a1
3a2
3b2
11
35
23
2b
2c–f
A
[a] After column chromatography.
For the 3-oxapentamethylene series, which yielded both
diastereomers, the relative stereochemistry was established
by means of
a combination of chemical-derivatization
(Scheme 8), spectroscopic, and molecular-modeling tech-
Under optimized McMurry pinacol coupling conditions,
the macrocyclized products were obtained when no nitro
groups were present (Scheme 7, right). In the presence of a
nitro group, complex reaction mixtures are produced, from
which no macrocyclized product could be isolated
(Scheme 7, left). We planned chemoselective reductions of
the nitro groups in the presence of the dialdehydes, but
failed attempts of McMurry reactions on model aminoben-
zaldehydes discouraged us from pursuing this approach fur-
ther.
As described, when the McMurry reaction is carried
under reflux, the diols are partly reduced to stilbenophane-
s.[20a] The olefins are not formed at room temperature and
mixtures of isomeric glycols are produced in good yields, al-
though they were strongly retained by the silica gel, thus
lowering the yields of the isolated products. The bimolecular
McMurry pinacol reaction is usually not very stereoselec-
tive[27] and produces diastereomeric mixtures of pinacols.
Furthermore, when this reaction is carried out on linked di-
carbonyl compounds, the product stereochemistry heavily
depends on the precursors: cis diols usually result when
small rings are formed, but the trans stereochemistry pre-
dominates for ring sizes of ten or above.[28] However, many
exceptions to these rules are observed and are attributed to
either substrate control or the reaction conditions.[29] In our
case, the two possible diastereomers are formed for the 3-
oxapentamethylene spacer and only one isomer was formed
for the hexamethylene (Table 1).
Scheme 8. Derivatization of macrocyclic pinacols. Conditions (1 equiv=
1 mol per mol): i) 2,2-dimethoxypropane (20 equiv), trimethylsilyl chlo-
ride (cat.), THF (dry), room temperature, 24 h; ii) Ac2O (large excess),
pyridine.
niques.[30] Treatment of the diol mixtures with acetic anhy-
dride yields the two diacetates (4a1 and 4a2), which are
more readily purified. To ascertain the relationship between
the diols and the diacetates, they were hydrolyzed to their
parent diols after isolation. Analogously, the mixture of
diols was treated with 2,2-dimethoxypropane in the presence
of catalytic trimethylsilyl chloride in an attempt to achieve
the corresponding dioxolanes. Both diols reacted, but only
one (5a1) of the two possible dioxolanes was formed. Ex-
amination of molecular models of the substrates suggests
that the diol that forms the dioxolane is the cis isomer. To
determine which diol was the precursor of the dioxolane,
they were also formed from the isolated diols, and the
minor isomer (3a1) was found
to form the dioxolane. We at-
tributed the reluctance of the
putative trans diol to form the
dioxolane to the conformation-
al restriction imposed by mac-
rocyclization, as both the syn
and anti pinacols derived from
combretastatin A4 form their
corresponding dioxolanes.[12,31]
Spectroscopic studies: The 1H
and 13C NMR spectra of the
macrocyclized products show a
distinct signal for each proton
Scheme 7. Synthesis of the macrocyclic pinacols. Conditions (1 equiv=1 mol per mol): 1) [TiCl4]–Zn (5–
10 equiv/10–22 equiv), THF (dry), room temperature, 30 min; 2) addition of 2 in THF dropwise, 3–5 h (5–55%
of 3 after purification). Pale gray: not obtained/isolated compounds.
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R. Pelµez, M. Medarde et al.
or carbon atom of the chemically equivalent pairs. This be-
havior implies a decrease in the exchange rate of such pairs
relative to the parent dialdehydes and the model nonmacro-
cyclic combretastatins, such that they slowly exchange on
the NMR timescale. The two distinct signals for each of the
equivalent aromatic proton pairs and the two methoxy
groups in the macrocycles for the cis isomer can either be
explained by two different slowly exchanging equally popu-
lated conformations (Scheme 9, option A) or by two differ-
ent chemical environments at each side of each phenyl ring
slowly exchanging by ring rotation on the NMR timescale,
thus preventing signal averaging (Scheme 9, option B). The
first hypothesis was discarded on the basis of the correlation
spectra, which showed extensive cross-peaks between atoms
that should otherwise be in different slowly exchanging con-
formations (e.g., the HA1=HA2 signal should not correlate
with the HA1’=HA2’ signal according to Scheme 9, option A).
Furthermore, two different signals should be observed for
the bridge protons HD and HD’ and for HT and HT’ in option
A of Scheme 9, which is not the case. Whereas small para-
cyclophanes (e.g., [2.2]paracyclophane) are highly constrain-
ed molecules, the ring strain of [2.7]- or [2.8]paracy-
clophanes, such as those described herein, should be far less
important. The interference of the methoxy groups on the
aromatic ring with the linker and the conformational prefer-
ences of the pinacol subunit must both contribute to the in-
creased rotational barrier of the phenyl rings, as the ana-
logue stilbenophanes do not show such behavior.[20a] The
same applies for the trans isomers.
3b2, 4b2, and 5a1 was based on the observed NOE interac-
tions between the hydrogen atoms on the bridge and the ar-
omatic protons (Scheme 10) and the value of the coupling
Scheme 10. Characteristic NOE interactions for either cis or trans macro-
cycles.[32]
constants between the bridge protons (Table 2and see
Scheme 10 for proton identity). The observation that in one
isomer the two hydrogen atoms on the bridge (HT and HD)
have NOE interactions with the most upfield shifted ortho
aromatic protons of each ring (HA2 and HB2), whereas the
most downfield shifted ortho protons of each aromatic ring
(HA1 and HB1) have NOE interactions with each other is
only compatible with a cis isomer (Schemes 9 and 10 cis and
Table 2: 3a1, 4a1, and 5a1). The other isomer (Scheme 10
trans) showed NOE interactions between each benzylic
proton on the bridge and its upfield shifted ortho aromatic
À
À
Each pinacol and its corresponding diacetate show very
small differences in their NMR spectra (except for those ex-
pected for the replacement of a hydroxy by an acetate
group), thus suggesting very similar structures and behavior
for both derivatives. The stereochemical assignment for the
isomeric pairs 3a1–3a2 and 4a1–4a2 and for the compounds
proton (HT HA2 and HD HB2) and the downfield shifted
À
À
proton on the opposite aromatic ring (HT HB1 and HD
A1); thus, this isomer was assigned as trans. These assign-
H
ments were consistent with larger coupling constants for the
benzylic protons in the trans isomers, with their chemical re-
activity in the transketalation reaction with dimethoxyace-
tone, and with the preferential
formation of trans isomers for
rings larger than ten members
in related pinacol reactions.[28]
The comparison of the
NMR spectra of the 3-oxapen-
tamethylene cis and trans gly-
cols with the only hexamethy-
lene-linked
glycol
formed
(3b2) strongly suggests a trans
relative stereochemistry for
the latter one (Table 2). The
1H and 13C NMR spectra of
3b2 and its diacetate 4b2 show
substantial line broadening of
the signals that correspond to
the disubstituted phenyl ring,
thus precluding their assign-
ment and reflecting a barrier
to exchange of the disubstitut-
ed phenyl ring lower than for
Scheme 9. Possibilities for the conformational equilibrium of 3a or 4a (cis). Option A: two bridge conforma-
tions in slow exchange with fast ring rotation; option B: two bridge conformations in fast exchange with slow
ring rotation.
the
3-oxapentamethylene-
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Conformational Behavior Study of Macrocycle Stilbenes
FULL PAPER
Table 2. Relevant NMR spectroscopic data and the deduced macrocycle relative stereochemistry.
results for uncyclized related
compounds, such as dihydro-
benzoins. These simple mole-
cules show preference for both
synclinal conformations for the
meso form (corresponding to
the cis diol) but prefer the syn-
clinal conformation in which
the two hydroxy groups are
gauche to each other for the
dl form (corresponding to the
trans isomer). The shorter 3-
Compound
3a1
3a2
3b2
4a1
4a2
4b2
5a1
HA1
HA2
HB1
HB2
HC1
HC2
HT
HD
6.19
5.67
6.95
6.36
6.69
6.59
4.75
4.83
5.0
3.63
3.623.39
0.01
cis
HA2:HD
HA2:HT
HA2:HB2
HB2:HD
HB2:HT
6.47
5.37
7.13
6.08
6.63
6.51
4.40
4.524.61
7.0
3.70
3.49
0.31
trans
6.60
5.68
6.11
5.90
6.94
6.55
6.78
6.70
6.05
6.43
5.626.04
7.17
6.36
6.74
6.50
6.32
5.80
6.4–7.4
6.4–7.4
6.4–7.4
6.4–7.4
4.55
6.3–6.8
6.3–6.8
6.3–6.8
6.3–6.8
5.93
6.92
6.61
6.66
6.61
5.36
6.66
5.74
6.08
5.84
6.00
7.6
5.44
Jbridge [Hz]
MeO
MeO
7.6
3.81
3.69
0.320.01
5.28.28.8
3.70
3.85
3.823.75
3.65
3.54
3.60
2 0.100.2
trans
HA1:HD
HA2:HT
HA2:HB1
HB2:HD
HB1:HT
Dd
A
0.31
stereochemistry
relevant
NOE interactions
trans
cis
trans
cis
oxapentamethylene
bridge
HA2:HD
HA2:HT
HA2:HB2
HB2:HD
HB2:HT
HA1:HB1
HA1:HD
HA2:HT
HB2:HD
HB1:HT
HA2:HD
HA2:HT
HB2:HD
HB2:HT
leads to somewhat more rigid
structures than the longer hex-
amethylene bridge, which pop-
ulates more conformations in
the macrocycles, which is in
good agreement with the NMR
spectroscopic data. The models
linked macrocycles. No improvement of the spectral quality
was noted when the temperature was varied from À30 to
608C in CDCl3. We attribute such a behavior to a more flex-
ible situation that arises from the longer linker, thus allow-
ing the less bulky disubstituted phenyl ring to populate sev-
eral conformations of similar energy to lead to complex
spectra at either lower or higher temperatures. The stereo-
chemistry was thus assigned by comparison with the better
resolved spectra of the 3-oxapentamethylene analogue. For
a related system, we previously reported the formation of a
single diastereomer with trans stereochemistry,[20b] which is
expected for an 18-membered ring.[28]
also explain the observed NOE interactions and coupling
constants.
In the trans analogues, two distinct signals for each of the
equivalent aromatic proton pairs (HA1–HA2, HB1–HB2, and
HC1–HC2) and the two methoxy groups can be explained by
the different chemical environments they are exposed to as
a result of slow ring rotation on the NMR timescale that
prevents signal averaging. The upfield shift of the protons or
methoxy groups on one side of each aromatic ring (HA2 and
its nearby methoxy group, and HB2 and less so, HC2) are
caused by the nearby aromatic ring. Two conformations are
predicted by the models for the cis isomers, and they must
exchange quickly on the NMR timescale to produce a single
set of resonances.
Conformational analysis: Molecular-mechanics calculations
showed a single low-energy conformation for the bridge of
the trans isomers and two energetically very close conforma-
tions for the bridge for the cis isomers. (In Scheme 11 only
the upper or the lower half of Scheme 9 has to be consid-
ered to account for the NMR spectra, as both halves would
lead to identical spectra.) In every case, and forced by the
length of the spacer, the two phenyl rings are gauche to
each other, thus corresponding to synclinal conformations.[33]
These results agree with experimental[34] and theoretical[35]
The most remarkable differences between the cis and
trans isomers are the differences in the proton chemical
shifts between the two chemically equivalent methoxy
groups (a very small difference for the cis isomers and a
larger one of more than 0.2ppm in the trans isomers;
Scheme 12); between the chemically equivalent protons
ortho to the bridge for each aromatic ring (same trend as
before); and the upfield shift of the benzylic protons in the
trans isomers with respect to the cis isomers (for both the pi-
nacols and the diacetates). For
the 13C NMR spectra, the main
differences in chemical shift
between the isomers corre-
spond to an expected upfield
shift of benzylic positions of
the cis isomers,[36] and a larger
difference in chemical shift be-
tween the chemically equiva-
lent aromatic carbon atoms.
These differences can be ex-
plained by the conformational
Scheme 11. The calculated most stable conformation for either a trans (a) or cis (b1 and b2) macrocycle (see
text). For clarity, the HB protons behind the phenyl rings in bold have been omitted (for labeling conventions
see ref. [32].
equilibrium
depicted
in
Scheme 11. Thus, the described
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R. Pelµez, M. Medarde et al.
1
Scheme 12. Most remarkable differences in chemical shift in the H NMR spectra between the cis and trans isomers.
exchange process in the cis isomer places the aromatic pro-
tons in the shielding cone of the other ring in only one of
the two conformations (e.g., HA1 is shielded in Scheme 11b1
but not in Scheme 11b2, and the opposite applies for its
counterpart HA2), thus decreasing the differences in chemi-
cal shift between the chemically equivalent proton pairs, rel-
ative to the trans analogues. The protons on the same side
of the bridge oxygen atoms (e.g., HA1, HB1, and HC1) are de-
shielded with respect to their counterparts on the opposite
side (e.g., HA2, HB2, and HC2; Scheme 11). Accordingly, the
bridge protons (HT and HD) have NOE interactions with the
more upfield shifted protons on the phenyl rings (which are
on the same side, as described), instead of one unshielded
and one shielded proton, as we would expect for a single
conformation (e.g., HT with HB2, which in the single confor-
mation depicted in Scheme 11b2should be unshielded, and
HA2, which should be shielded) as that observed for the
trans isomers (HB1 and HA2 in Scheme 11a). The shielding of
the bridge protons in the trans isomer with respect to the cis
isomer can be explained by the shielding effect of the
Conclusion
In conclusion, the synthesis of a new family of [2.7]- and
[2.8]cyclophanes, conformationally restricted macrocyclic
analogues of dihydroxydeoxycombretastatin A4, has been
completed. The relatively small increase in molecular
volume produced by the additional atoms between the rings
makes them very similar in size to their parent compounds,
and the restrictions imposed on both aromatic rings relative
to related active dihydrocombretastatins turns them into
suitable probes of the geometry of combretastatins when
bound to tubulin. The spectroscopic analysis of these com-
pounds shows the existence of severe restrictions to the ro-
tation of their aromatic rings, thus allowing us to establish
the conformational equilibria for cis and trans isomers. The
results of molecular-dynamics simulations fully agree with
the interpretation of the NMR evidence. The synthetic ach-
ievements and conformational knowledge obtained herein
will allow us to design new members of this type of com-
pound with different conformational bias, which are being
pursued in our laboratory to test their biological properties.
À
gauche C OR bond, which only occurs 50% of the time for
the cis isomers (HD is anti to the OR bond in Scheme 11b1
and gauche in Scheme 11b2).
To further investigate the conformational behavior of
these pinacols, the cis and trans isomers with the 3-oxapen-
tamethylene spacer and the trans hexamethylene-linked
glycol were submitted to molecular dynamic (MD) simula-
tions at virtual temperatures of 300, 400, 600, 1000, 1200,
and 1500 K, with simulations lengths of 1–3 ns. The behavior
of the bridges and the aromatic rings in the resulting trajec-
tories were analyzed. At 300–600 K (Figure 1A and B), the
rotational barriers of the bridges are easily surmounted in
both the cis and trans (gauche OH-C-C-OH conformation
predominates) isomers but none of the aromatic rings rotate
(Figure 1C), in good agreement with the observed NMR
spectra and the proposed conformational equilibrium. At
higher temperatures (1200 K and above), the disubstituted
phenyl ring can rotate in the hexamethylene-linked glycol
(Figure 1D), thus indicating a higher flexibility of the mac-
rocycles with the longer spacer, but for the 3-oxapenta-
methylene series, no ring rotation was observed even at the
highest virtual temperature tested (1500 K). The observed
line broadening for the disubstituted phenyl ring of 3b2 can
thus be explained.
Experimental Section
General: Reagents were used as purchased without further purification.
Solvents (THF, N,N-dimethylformamide (DMF), CH2Cl2, and benzene)
were dried and freshly distilled before use according to literature proce-
dures. Chromatographic separations were performed by flash column
chromatography on silica gel (Kieselgel 40, 0.040–0.063; Merck) or by
gravity column chromatography (Kieselgel 60, 0.063–0.200 mm; Merck).
TLC analysis was performed on precoated polyester plates of silica gel
(thickness: 0.25 mm) with fluorescent indicator UV 254 (Polychrom SI
F254). Melting points were determined on a Buchi 510 apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 on a
Bruker WP 200-SY spectrometer at 200/50 MHz or on a Bruker SY spec-
trometer at 400/100 MHz. Chemical shifts (d) are given in ppm downfield
from tetramethylsilane as the internal standard and the coupling con-
stants (J values) are given in hertz. IR spectra were recorded on a Nicolet
Impact 410 Spectrophotometer. GC–mass-spectrometric analysis was car-
ried out in a Hewlett–Packard 5890 Serie II apparatus (70 eV). For fast-
atom-bombardment high-resolution mass-spectrometry (FAB-HR-MS), a
VG-TS250 apparatus (70 eV) was used. HPLC analysis was run on at
least three different columns (5 mm, 4.6”150 mm): Waters X-Terra MS
C8 , Waters X-Terra MS C18, and Waters X-Terra MS CF on an Agilent
HP series 1100 with at least two different solvent gradients (typically ace-
tonitrile/water or methanol/water). Elemental analyses were recorded on
a Perkin Elmer 2400 CHN apparatus.
General procedure for the Mitsunobu reactions yielding hydroxyalde-
hydes (1) and dialdehydes (2): A mixture of the phenolic aldehyde, the
7252
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7246 – 7256

Conformational Behavior Study of Macrocycle Stilbenes
FULL PAPER
Figure 1. Graphical summary of the molecular dynamics simulation trajectories. A) Histograms and B) Trajectories of the bridge dihedral angles for cis-
3a1 (left) and trans-3b2 (right) diols at 600 K. Trajectories at 600 (C) and 1500 K (D) of the dihedral angle between the disubstituted phenyl ring (left)
and the tetrasubstituted ring (right) and the bridge for 3b2. The ring flip is indicated by an arrow. The relevant dihedral angles are highlighted in the ac-
companying structures.
Chem. Eur. J. 2007, 13, 7246 – 7256
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7253

R. Pelµez, M. Medarde et al.
PPh3 resin (1.0 mol per mol of aldehyde), and a large excess of the diol
(5.0 mol per mol of aldehyde) in dry CH2Cl2 (10 mL per mmol of alde-
hyde) was stirred for 1 h before the slow addition of DBAD or DIAD
(1.21 mol per mol of aldehyde) at room temperature. After 48 h, the re-
action mixtures were filtered and the resin washed with ethyl acetate.
The combined organic layers were evaporated, dissolved in ethyl acetate,
and washed with NaOH (4%) and brine to neutrality. Once dried and
evaporated, the crude reaction products were used in the next Mitsunobu
reaction or purified by flash chromatography (hexane/ethyl acetate sol-
vent mixtures) for characterization purposes. Using the same procedure
used to prepare the hydroxyaldehydes (1), the (crude) reaction products
were treated with 1.1 moles of phenolic aldehyde per mole of 1 to pro-
duce the dialdehydes (2).
6.0 Hz, 2H), 6.96 (d, J=8.8 Hz, 1H), 7.58 (d, J=1.7 Hz, 2H), 7.79 (d, J=
8.8 Hz, 1H), 7.79 (d, J=1.7 Hz, 2H), 9.83 (s, 1H), 9.89 (s, 1H) ppm.
4-{2-[2-(4-Formyl-2-nitrophenoxy)ethoxy]ethoxy}-3,5-dimethoxybenzalde-
hyde (2e): Obtained as an oily compound 47% in yield. 1H NMR
(400 MHz): d=3.72(s, 6H), 4.12(m, 6H), 4.2(m, 2H), 7.02(s, 2H),
7.14 (d, J=8.7 Hz, 1H), 7.87 (dd, J=8.7, 1.8 Hz, 1H), 8.12(d, J=1.8 Hz,
1H), 9.65 (s, 1H), 9.73 (s, 1H) ppm; 13C NMR (100.6 MHz): d=58.0 (2)
(CH3), 69.0 (CH2), 69.5 (CH2), 70.9 (CH2), 72.4 (CH2), 106.5 (2)(CH),
115.1 (CH), 126.9 (CH), 129.0 (C), 131.7 (C), 134.7 (CH), 139.8 (C),
142.4 (C), 154.0 (2)(C), 156.4 (C), 190.0 (CHO), 191.1 (CHO) ppm.
4-[6-(4-Formyl-2-nitrophenoxy)hexoxy]-3,5-dimethoxybenzaldehyde (2 f):
Obtained as an oily compound in 62% yield. 1H NMR (400 MHz): d=
1.59 (m, 4H), 1.85 (m, 4H), 3.91 (s, 6H), 4.12(t, J=7.0 Hz, 2H), 4.26 (t,
J=6.1 Hz, 2H), 7.13 (s, 2H) 7.29 (d, J=8.7 Hz, 1H), 8.06 (dd, J=8.7,
1.8 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 9.84 (s, 1H), 9.91 (s, 1H) ppm;
4-[2-(2-Hydroxyethoxy)ethoxy]benzaldehyde (1a): An oily compound
was obtained in 76% yield. 1H NMR (400 MHz): d= 3.60 (m, 2H), 3.68
(m, 2H), 3.80 (m, 2H), 4.12 (m, 2H), 6.90 (m, 2H), 7.73 (m, 2H), 9.76 (s,
1H) ppm; 13C NMR (100.6 MHz): d=61.6 (CH2), 67.7 (CH2), 69.3 (CH2),
72.8 (CH2), 114.8 (2) (CH), 130.0 (C), 132.0 (2) (CH), 163.8 (C), 191.0
13C NMR (100.6 MHz): d=25.3 (2)
(2)(CH3), 70.2(CH ), 73.2(CH ), 106.5 (2)(CH), 114.6 (CH), 126.8 (CH),
128.6 (C), 131.5 (C), 134.7 (CH), 139.7 (C), 142.7 (C), 153.7 (2)(C), 156.5
(C), 189.0 (CHO), 191.0 (CHO) ppm; FT-IR: n˜ =1686 cmÀ1
A
AHCTREUNG
2
2
(CHO) ppm; FT-IR: n˜ =3306, 1705 cmÀ1 GC-MS: m/z: 210 ([M+],
;
.
92%).
General procedure for McMurry reactions yielding pinacols 3: A mixture
of [TiCl4]·2THF (97%; 5 mol per mol of dialdehyde) and Zn (5 mol per
mol of dialdehyde) in dry THF (30 mL per mmol of dialdehyde) was pre-
pared at 08C and heated to reflux for 30 min. A solution of dialdehydes
2a–f in dry THF (5 mL per mmol of dialdehyde) was added and the reac-
tion mixture maintained at either room temperature (no olefin forma-
tion) or heated to reflux for 3 h. The reaction was poured into a mixture
of ethyl acetate and 2m HCl, the aqueous layer extracted, and the com-
bined organic layers worked up. Products were separated by chromatog-
raphy (SiO2, hexane/ethyl acetate mixtures with 0.1% triethylamine).
4-[2-(2-Hydroxyethoxy)ethoxy]-3-nitrobenzaldehyde (1b): Obtained as
an oily compound in 64% yield. 1H NMR (400 MHz): d=3.73 (m, 4H),
3.95 (t, J=4.8 Hz, 2H), 4.38 (t, J=4.8 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H),
8.08 (dd, J=7.5, 1.8 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 9.92(s, 1H) ppm;
13C NMR (100.6 MHz): d=61.8 (CH2), 68.9 (CH2), 69.9 (CH2), 72.9
(CH2), 114.9 (CH), 127.5 (CH), 128.4 (C), 129.2 (C), 134.7 (CH), 156.4
(C), 188.8 (CHO) ppm; FT-IR: n˜ 3306, 1700 cmÀ1
.
4-(6-Hydroxyhexoxy)-3-nitrobenzaldehyde (1c): Obtained as an oily
compound in 89% yield. H NMR (400 MHz): d=1.50 (m, 4H), 1.85 (m,
1
(2RS,3SR)-6,20-Dimethoxy-8,11,14-trioxatricyclo[13.2.2.24,7]henicosa-
1(17),4,6,15,18,20-hexaene-2,3-diol (3a1): Obtained as an oily compound
in 11% yield. 1H NMR (400 MHz): d=3.55 (m, 2H), 3.60 (m, 2H), 3.62
(s, 3H), 3.63 (s, 3H), 4.10 (m, 2H), 4.18 (m, 2H), 4.75 (d, J=5.0 Hz,
1H), 4.83 (d, J=5.0 Hz, 1H), 5.67 (bs, 1H), 6.19 (bs, 1H), 6.36 (dd, J=
8.4, 1.8 Hz, 1H), 6.59 (dd, J=8.4, 2.5 Hz, 1H), 6.69 (dd, J=8.6, J=
2.5 Hz, 1H), 6.95 (dd, J=8.6, 1.8 Hz, 1H) ppm; 13C NMR (100.6 MHz):
d=55.5 (CH3), 55.7 (CH3), 66.8 (CH2), 73.1 (CH2), 73.4 (CH2), 73.5
(CH2), 75.6 (CH), 76.0 (CH), 102.2 (CH), 103.3 (CH), 113.5 (CH), 114.9
(CH), 126.0 (CH), 127.0 (CH), 131.1 (C), 135.6 (C), 136.7 (C), 151.8 (C),
152.7 (C), 157.9 (C) ppm; FT-IR: n˜ =3453, 1608 cmÀ1; HR-MS (EI): calcd
(C20H24O7): 376.1522; found: 376.1551.
4H), 3.63 (t, J=6.0 Hz, 2H), 4.19 (t, J=6.0 Hz, 2H), 7.19 (d, J=7.8 Hz,
1H), 8.04 (dd, J=2.2, 7.8 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 9.90 (s,
1H) ppm; 13C NMR (100.6 MHz): d=25.3 (CH2), 25.5 (CH2), 28.6 (CH2),
32.4 (CH2), 62.3 (CH2), 70.3 (CH2), 114.7 (CH), 126.9 (CH), 128.6 (C),
135.1 (C), 139.7 (CH), 156.7 (C), 189.3 (CHO) ppm; FT-IR: n˜ =3254,
1700 cmÀ1
4-[2-(2-Hydroxyethoxy)ethoxy]-3-methoxy-5-nitrobenzaldehyde
.
(1d):
Obtained as an oily compound in 82% yield. 1H NMR (400 MHz): d=
3.61 (m, 2H), 3.69 (m, 2H), 3.82 (t, J=4.4 Hz, 2H), 3.99 (s, 3H), 4.43 (t,
J=4.4 Hz, 2H), 7.61 (d, J=1.7 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 9.91 (s,
1H) ppm; 13C NMR (100.6 MHz): d=56.7 (CH3), 61.7 (CH2), 70.0 (CH2),
72.6 (CH2), 73.9 (CH2), 113.4 (CH), 119.6 (CH), 144.9 (C), 147.0 (C),
(2RS,3RS)-6,20-Dimethoxy-8,11,14-trioxatricyclo[13.2.2.24,7]henicosa-
1(17),4,6,15,18,20-hexaene-2,3-diol (3a2): Obtained as an oily compound
in 35% yield. 1H NMR (400 MHz): d=3.38 (m, 1H), 3.39 (s, 3H), 3.65
(m, 2H), 3.70 (s, 3H), 3.82 (m, 3H), 4.16 (m, 1H), 4.33 (m, 1H), 4.40 (d,
J=7.0 Hz, 1H), 4.52(d, J=7.0 Hz, 1H), 5.37 (bs, 1H), 6.08 (bd, J=
8.4 Hz, 1H), 6.47 (bs, 1H), 6.51 (bd, J=8.4 Hz, 1H), 6.63 (bd, J=8.0 Hz,
1H), 7.13 (bd, J=8.0 Hz, 1H) ppm; 13C NMR (100.6 MHz): d=55.1
(CH3), 56.0 (CH3), 66.7 (CH2), 73.0 (CH2), 73.4 (CH2), 73.5 (CH2), 81.3
(CH), 82.2 (CH), 101.5 (CH), 105.2 (CH), 112.5 (CH), 116.5 (CH), 125.4
(CH), 128.7 (CH), 131.9 (C), 136.3 (C), 136.7 (C), 152.2 (C), 152.4 (C),
154.5 (C), 156.5 (C), 189.2(CHO) ppm; FT-IR: n˜ : 3258, 1691 cmÀ1
.
4-(6-Hydroxyhexoxy)-3-methoxy-5-nitrobenzaldehyde (1e): Obtained as
an oily compound in 86% yield. 1H NMR (400 MHz): d=1.49 (m, 4H),
1.60 (dd, J=6.1, 7.0 Hz, 2H), 1.79 (m, 2H), 3.64 (t, J=5.7 Hz, 2H), 4.00
(s, 3H), 4.24 (t, J=6.6 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.81 (d, J=
1.7 Hz, 1H), 9.90 (s, 1H) ppm; 13C NMR (100.6 MHz): d=25.4 (2)
(CH2), 29.9 (CH2), 32.6 (CH3), 56.7 (CH2), 62.7 (CH2), 75.2(CH 2), 113.4
(CH), 119.6 (CH), 144.9 (C), 147.3 (C), 154.8 (C), 156.6 (C), 189.2
(CHO) ppm; FT-IR: n˜ =3288, 1703 cmÀ1
.
157.8 (C) ppm; FT-IR: n˜ =3403, 1608 cmÀ1
; HR-MS (EI): calcd
4-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxybenzaldehyde (1 f):[20a] Ob-
(C20H24O7): 376.1522; found: 376.1501.
tained as an oily compound in 73% yield.
(2RS,3RS)-6,21-Dimethoxy-8,15-dioxatricyclo[14.2.2.24,7]docosa-
4-(6-Hydroxyhexoxy)-3,5-dimethoxybenzaldehyde (1g):[20a] Obtained as
1(18),4,6,16,19,21-hexaene-2,3-diol (3b2): Obtained as an oily compound
in 23% yield. H NMR (400 MHz): d=1.1–1.6 (m, 8H), 3.8–4.2(m, 4H),
an oily compound in 70% yield.
1
4-{2-[2-(4-Formylphenoxy)ethoxy]ethoxy}-3,5-dimethoxybenzaldehyde
3.49 (s, 3H), 3.81 (s, 3H), 4.55 (d, J=7.6 Hz, 1H), 4.61 (d, J=7.6 Hz,
1H), 5.68 (bs, 1H), 6.60 (bs, 1H), 6.4–7.2(m, 4H) ppm; 13C NMR
(100.6 MHz): d=23.6 (CH2), 23.7 (CH2), 25.7 (CH2), 27.0 (CH2), 55.4
(CH3), 56.2(CH 3), 67.6 (CH2), 71.5 (CH2), 80.7 (CH), 81.5 (CH), 102.4
(CH), 106.0 (CH), 114.2 (2) (CH), 128.1 (2) (CH), 132.3 (C), 134.5 (C),
(2a):[20a] Obtained as an oily compound in 80% yield.
4-[6-(4-Formylphenoxy)hexoxy]-3,5-dimethoxybenzaldehyde
Obtained as an oily compound in 62% yield. M.p (hexane/Et2O) 2758C.
(2b):[20a]
4-{2-[2-(4-Formylphenoxy)ethoxy]ethoxy}-3-methoxy-5-nitrobenzalde-
hyde (2c): Obtained as an oily compound in 20% yield. 1H NMR
(400 MHz): d=3.92(s, 3H), 4.18 (m, 4H), 4.30 (m, 2H), 4.42(m, 2H),
6.96 (d, J=8.0 Hz, 1H), 7.52(d, J=1.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),
7.80 (d, J=1.8 Hz, 1H), 9.81 (s, 1H), 9.83 (s, 1H) ppm.
135.2(C), 15.2(C), 153.5 (C), 156.8 (C) ppm; FT-IR:
n˜ =3435,
1608 cmÀ1; HR-MS (EI): calcd (C22H28O6): 388.1886; found: 388.1897.
Acetylation reactions: Either a mixture of isomeric alcohols 3a1 and 3a2
or each one by itself and alcohol 3b2 were dissolved in pyridine (1 mL
per mmol of alcohol) and treated with acetic anhydride (1 mL per mmol
of alcohol). After 2h, the mixture was diluted with ethyl acetate and ex-
tracted with 2m HCl, 5% NaHCO3, and brine. The combined organic
4-[6-(4-Formylphenoxy)hexoxy]-3-methoxy-5-nitrobenzaldehyde
Obtained in 25% yield. M.p. (hexane/Et2O) 2758C; H NMR (400 MHz):
d=1.5–1.9 (m, 8H), 3.90 (s, 3H), 4.00 (t, J=6.0 Hz, 2H), 4.24 (t, J=
(2d):
1
7254
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7246 – 7256

Conformational Behavior Study of Macrocycle Stilbenes
FULL PAPER
layers were dried over anhydrous Na2SO4, filtered, and the solvent rotary
evaporated. If necessary, the products were separated by chromatography
(SiO2, hexane/ethyl acetate mixtures with 0.1% triethylamine).
1610 cmÀ1
;
GC-MS: m/z: 416 ([M+], 100); HRMS (EI): calcd for
C22H27NaO5: 439.1733; found: 439.2538.
(2RS,3SR)-6,20-Dimethoxy-8,11,14-trioxatricyclo[13.2.2.24,7]henicosa-
1(17), 4,6,15,18,20-hexaene-2,3-diyl diacetate (4a1): Obtained as an oily
compound in 60% yield. 1H NMR (400 MHz): d=2.20 (s, 3H), 2.21 (s,
3H), 3.60 (m, 2H), 3.67 (m, 2H), 3.69 (s, 3H), 3.70 (s, 3H), 4.09 (ddd,
J=2.8, 5.2, 13.6 Hz, 1H), 4.15 (ddd, J=2.8, 5.2, 13.6 Hz, 1H), 4.22 (ddd,
J=2.5, 6, 14.0 Hz, 1H), 4.28 (ddd, J=2.8, 5.2, 14.0 Hz, 1H), 5.90 (d, J=
1.7 Hz, 1H), 6.05 (d, J=5.2Hz, 1H), 6.08 (d, J=5.2Hz, 1H), 6.11 (d, J=
1.7 Hz, 1H), 6.55 (dd, J=8.4, 2.0 Hz, 1H), 6.70 (dd, J=8.5, 2.7 Hz, 1H),
6.78 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (dd, J=8.7, 2.2 Hz, 1H) ppm;
13C NMR (100.6 MHz): d=21.0 (2) (CH3), 55.6 (CH3), 55.8 (CH3), 66.7
(CH2), 73.3 (CH2), 73.8 (CH2), 73.9 (CH2), 75.0 (CH), 75.1 (CH), 102.8
(CH), 103.9 (CH), 113.8 (CH), 115.2 (CH), 126.6 (CH), 127.0 (CH),
127.6 (C), 131.4 (C), 137.6 (C), 152.2 (C), 153.0 (C), 158.3 (C) 169.8 (2)
(C) ppm; FT-IR: n˜ =1747, 1610 cmÀ1; GC-MS: m/z: 460 ([M+], 22);
HRMS (EI): calcd for C24H28O9: 460.1733; found: 460.1734; elemental
analysis (%) calcd: C 62.60, H 6.13; found: C 62.78, H 6.30.
Acknowledgements
We thank the MEC (Ref CTQ2004–00369/BQU), Junta de Castilla y
León (SA090 A06), and the EU (Structural Funds) for financial support.
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3H), 3.50 (m, 1H), 3.53 (m, 1H), 3.54 (s, 3H), 3.63 (m, 1H), 3.75 (ddd,
J=11.2, 6.8, 2.3 Hz, 1H), 3.85 (s, 3H), 3.98 (ddd, J=13.3, 6.8, 2.2 Hz,
1H), 4.00 (ddd, J=13.9, 2.6, 1.6 Hz, 1H), 4.25 (ddd, J=2.3, 4.6, 13.3 Hz,
1H), 4.45 (bdd, J=8.0, 13.9 Hz, 1H), 5.62(d, J=1.7 Hz, 1H), 5.74 (d, J=
8.2Hz, 1H), 5.84 (d, J=8.2Hz, 1H), 6.36 (dd, J=2.2, 8.6 Hz, 1H), 6.43
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73.5 (CH2), 78.6 (CH), 79.5 (CH), 101.9 (CH), 106.0 (CH), 113.0 (CH),
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1610 cmÀ1
;
GC-MS: m/z: 460 ([M+], 23); HRMS (EI): calcd for
C24H28O9: 460.1733; found: 460.1756; elemental analysis (%) calcd: C
62.60, H 6.13; found: C 62.41, H 5.94.
(2RS,3RS)-6,21-Dimethoxy-8,15-dioxatricyclo[14.2.2.24,7]docosa-
1(18),4,6,16,19,21-hexaene-2,3-diyl diacetate (4b2): Obtained as an oily
compound in 57% yield. 1H NMR (400 MHz): d=1.1–1.8 (m, 8H), 2.10
(s, 3H), 2.11 (s, 3H), 3.60 (s, 3H), 3.8–4.2 (m, 4H), 3.82 (s, 3H), 5.93 (d,
J=8.8 Hz, 1H), 6.00 (d, J=8.8 Hz, 1H), 6.04 (d, J=1.6 Hz, 1H), 6.50 (d,
J=1.6 Hz, 1H), 6.4–7.4 (m, 4H) ppm; 13C NMR (100.6 MHz): d=21.1
(2) (CH3), 23.4 (CH2), 23.7 (CH2), 25.8 (CH2), 27.0 (CH2), 55.7 (CH3),
56.2(CH 3), 67.7 (CH2), 71.7 (CH2), 77.9 (CH), 78.6 (CH), 103.1 (CH),
107.3 (CH), 128.5 (C), 131.3 (C), 135.2 (C), 152.4 (C), 153.5 (C), 157.3
(C), 170.3 (2) (C) ppm, four CH resonances not observed; FT-IR: n˜ =
1744, 1610 cmÀ1
472.1990.
; HRMS (EI): calcd for C26H32O8: 472.2097; found:
Transketalation reactions: Either a mixture of isomeric alcohols 3a1 and
3a2 or each one by itself were dissolved in acetone (5 mL per mmol of
alcohol) and treated with 2,2-dimethoxypropane (50 mol per mol of
glycol) and trimethylsilyl chloride (0.1 mol per mol of glycol). After 20 h
at room temperature, the mixture was diluted with ethyl acetate and
washed with 5% NaHCO3, and brine. The combined organic layers were
dried over anhydrous Na2SO4, filtered, and the solvent rotary evaporated.
Products were separated by chromatography (SiO2, hexane/ethyl acetate
mixtures with 0.1% triethylamine).
(2RS,3SR)-2,3-Isopropylenedioxy-6,20-dimethoxy-8,11,14-trioxatricy-
clo[13.2.2.24,7]henicosa-1(17),4,6,15,18,20-hexaene (5a1): Obtained as an
oily compound in 65% yield. 1H NMR (400 MHz): d=1.61 (s, 3H), 1.83
(s, 3H), 3.53 (m, 2H), 3.62 (m, 2H), 3.65 (s, 3H), 3.75 (s, 3H), 4.17 (m,
2H), 4.23 (m, 2H), 5.36 (d, J=7.6 Hz, 1H), 5.44 (d, J=7.6 Hz, 1H), 5.80
(d, J=1.2Hz, 1H), 6.32 (d, J=1.2Hz, 1H), 6.61 (m, 2H), 6.66 (dd, J=
8.8, 2.0 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H) ppm; 13C NMR (100.6 MHz):
d=24.1 (CH3), 26.6 (CH3), 55.7 (CH3), 55.8 (CH3), 67.8 (CH2), 71.3
(CH2), 71.4 (CH2), 72.0 (CH2), 81.3 (CH), 81.6 (CH), 103.4 (CH), 104.1
(CH), 109.0 (C), 114.4 (CH), 114.9 (CH), 127.0 (CH), 127.4 (CH), 132.0
(C), 133.7 (C), 136.0 (C), 151.8 (C), 152.3 (C), 158.0 (C) ppm; FT-IR: n˜ :
Chem. Eur. J. 2007, 13, 7246 – 7256
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7255

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to the more downfield shifted proton: e.g., d
N
N
A
ACHTREUNG
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Received: February 27, 2007
Published online: June 13, 2007
7256
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Chem. Eur. J. 2007, 13, 7246 – 7256