Regiocontrolled synthesis and optical resolution of mono-, di-, and trisubstituted tribenzotriquinacene derivatives: Key building blocks for further assembly into molecular squares and cubes

Article abstract of DOI:10.1021/jo501904y

The regiocontrolled syntheses of four chiral C₁- or C₃-symmetrical tribenzotriquinacene (TBTQ) derivatives bearing methoxy or hydroxy groups at the peripheral positions [(2,6-(OMe)₂, (±)-18 and (±)-20; 2,6-(OH)₂

Full text of DOI:10.1021/jo501904y

Article
pubs.acs.org/joc
Regiocontrolled Synthesis and Optical Resolution of Mono‑, Di‑, and
Trisubstituted Tribenzotriquinacene Derivatives: Key Building Blocks
for Further Assembly into Molecular Squares and Cubes
Wen-Rong Xu,† Hak-Fun Chow,*,† Xiao-Ping Cao,*,‡ and Dietmar Kuck*,§
†Department of Chemistry, Center of Novel Functional Materials and State Key Laboratory of Synthetic Chemistry, The Chinese
University of Hong Kong, Shatin, Hong Kong SAR
‡State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
§Department of Chemistry, Bielefeld University, Universitatsstraße 25, 33615 Bielefeld, Germany
̈
S
* Supporting Information
ABSTRACT: The regiocontrolled syntheses of four chiral C1-
or C3-symmetrical tribenzotriquinacene (TBTQ) derivatives
bearing methoxy or hydroxy groups at the peripheral positions
[(2,6-(OMe)2, ( )-18 and ( )-20; 2,6-(OH)2, ( )-19; and
2,6,10-(OMe)3, ( )-21] by two different synthesis protocols
are reported. Compounds ( )-19, ( )-20, and ( )-21 and
two (already-known) monosubstituted C1-symmetrical TBTQ
analogues [2-OH ( )-23 and 2-OMe ( )-24] were readily
resolved by chiral HPLC, and their absolute configurations
were determined by X-ray crystallography and/or circular
dichroism (CD) studies. Optical resolution of three closely related TBTQ derivatives [2,6-(OMe)2, ( )-18; 2-OMe, ( )-22; and
2-OH, ( )-25] containing the same peripheral substituents but other bridgehead residues failed. Enantiopure TBTQ derivatives
of this sort are considered promising structural motifs toward the construction of molecular squares and cubes.
unit is a logical approach. Among all possible TBTQ
derivatives, a limited variety of congeners, namely, 1,5- (1)
and 2,6- (2) disubstituted derivatives, 1,5,9- (3) and 2,6,10- (4)
trisubstituted derivatives, 1,2,5,6- (5) and 2,3,6,7- (6)
tetrasubstituted derivatives, and finally 1,2,5,6,9,10- (7) and
2,3,6,7,10,11- (8) hexasubstituted derivatives that contain
functional groups oriented at orthogonal geometries could
serve as building blocks of molecular squares and cubes (Figure
1). Because of the high steric repulsion with the bridgehead
substituents and the opposite aromatic ring, introduction of
functionalities at the inner (1-, 4-, 5-, 8-, 9-, 12-) positions of
the TBTQ system is difficult.11,16 Hence, only derivatives 2, 4,
6, and 8 are easily accessible targets.
However, two inherent problems have to be resolved to
utilize these motifs. First, one has to develop regiocontrolled
synthetic methods toward such multiply functionalized TBTQs.
Based on our previous research results, it is known that the
introduction of functional group(s) by electrophilic aromatic
substitution of the parent TBTQ compounds 9 (R = Me or H)
invariably produces mixtures of regioisomeric products. For
example, two-fold formylation of the parent TBTQ derivative 9
(R = Me) gave an inseparable mixture of two Cs-symmetrical
and one C1-symmetrical diformyl derivatives 10, 12, and
INTRODUCTION
■
Molecular self-assembly utilizing simple molecular fragments
toward the synthesis of complex yet ordered molecular
architectures is one of the greatest achievements in supra-
molecular chemistry.1 Many of these self-organized systems
have already shown applications in the fields of controlled drug
delivery,2 molecular sensing,3,4 catalysis,5 and host−guest
complexation.6−8 Because the self-assembly process is entropi-
cally unfavorable, the success of this approach relies heavily on
the structural preorganization and geometrical matching of the
various building blocks. Among the many structural motifs, the
tribenzotriquinacene (TBTQ) skeletal system is of special
interest. Owing to the nearly orthogonal disposition of the
three indane ring systems,9,10 TBTQ derivatives are ideally
suited for the construction of molecular squares and cubes.11
Indeed, several studies involving the use of TBTQ compounds
to construct self-assembled systems have already appeared. For
examples, Volkmer and co-workers demonstrated that a C3v-
symmetrical TBTQ host12 and an optically pure C3-sym-
metrical TBTQ host13 can encapsulate a C60 guest molecule.
Georghiou’s and our groups also showed that C3v-symmetrical
TBTQ compounds can act as hosts for fullerenes such as C60
and C70.14,15
To construct larger systems such as molecular squares and
cubes that can accommodate larger or multiple guest molecules,
designing molecular self-assembles using more than one TBTQ
Received: August 18, 2014
Published: September 15, 2014
© 2014 American Chemical Society
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Figure 1. TBTQ derivatives that can be used to construct molecular squares and cubes.
Figure 2. Synthesis of 2,6-difunctionalized TBTQ derivatives ( )-11 and 2,6,10-trifunctionalized TBTQ derivatives ( )-14 by electrophilic aromatic
nitration or formylation.
Figure 3. TBTQ derivatives used in the formation of self-assemblies containing more than one TBTQ unit.
( )-11 (R = Me), respectively (Figure 2).17 Three-fold
nitration of 9 (R = H18 or Me19) produced a 3:1 mixture of
the C1- and C3-symmetrical trinitro-TBTQ isomers ( )-13 and
( )-14 (R = H or Me, X = NO2), respectively, whereas three-
fold formylation20 of 9 (R = Me) produced a 2:3 mixture of C1-
and C3-symmetrical trialdehydes ( )-13 and ( )-14 (R = H, X
= CHO), respectively. In both cases, tedious chromatographic
separations were required to isolate the regioisomers in pure
form. Gratifyingly, this regiochemistry issue was resolved by the
recent report by Hopf and co-workers,21 who demonstrated
that the C1-symmetric 2,6-disubstituted derivative ( )-2 and
the C3-symmetric 2,6,10-trisubstituted analogue ( )-4 could, in
principle, be prepared in a highly regioselective manner. The
second problem is associated with the inherent chirality of
some of these derivatives. Whereas the tetrasubstituted 6 and
hexasubstituted 8 are optically inactive, the 2,6-disubstituted
derivative ( )-2 and the 2,6,10-trisubstituted ( )-4 analogue
are inherently chiral. Hence, if the latter are to be used to
construct self-assemblies containing more than one TBTQ unit,
optically pure derivatives have to be used, unless a highly
enantioselective self-sorting22 could be realized during the self-
assembly process involving these racemates. Such a highly
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Figure 4. TBTQ derivatives synthesized in this study. Those included in the boxes are resolvable by chiral HPLC.
enantioselective self-sorting was observed once in our hands,
but it occurred during a crystallization process. In this case, the
racemic C3-symmetrical tribromotrinitro TBTQ derivative
( )-15 was found to form nanocubes by self-assembly of
eight molecules of the same enantiomer (Figure 3).18 However,
an enantioselective self-sorting of this type has never occurred
in the solution phase. For example, dynamic covalent synthesis
between the racemic C3-symmetrical trialdehyde ( )-16 and
optically pure (S,S)-diaminocyclohexane in a 2:3 molar ratio
afforded a nearly statistical (∼1:2:1) mixture of three
cryptophane derivatives.20 In this case, the major cryptophane
product was found to contain one molecule of (+)-16 and one
molecule of (−)-16. Of course, the problems of both
regioselectivity and optical resolution could be avoided if one
employed the C3v-symmetrical hexafunctionalized TBTQ
compound 8 as the building block. In fact, this was recently
demonstrated by Klotzbach et al. in the dynamic covalent
assembly of a nanocube from the condensation of the
2,3,6,7,10,11-hexahydroxy-TBTQ derivative 17 and 1,4-diphe-
nylenediboronic acid in a 2:3 stoichiometric ratio.23
become useful toward the construction of a large variety of
novel self-assembled systems.
RESULTS AND DISCUSSION
■
Regioselective Synthesis of C1-Symmetrical Dime-
thoxy- and Dihydroxy-TBTQ Derivatives ( )-18 and
( )-19 Using Kuck’s Method. In our reported synthesis of
the TBTQ parent compound, the key step involved in the
formation of the TBTQ skeleton 27 (X = H) was a double
cyclization reaction from the 1,3-indanediol 26 (X = H)
(Scheme 1).11,24 It was envisaged that proper positioning of the
Scheme 1. Double Cyclization Strategy toward the 2,5-
Difunctionalized TBTQ Skeleton by Kuck’s Method
To expand the application of TBTQ compounds (see Figure
4), it is necessary to develop methods that can prepare 2,6-
disubstituted and 2,6,10-trisubstituted TBTQ derivatives with
good regioselectivity and in optically pure form. Herein, we
report some important progress toward such aims by (i)
developing a regiocontrolled entry to the C1-symmetrical 2,6-
dimethoxy- and 2,6-dihydroxy-TBTQ derivatives ( )-18 and
( )-19, respectively, by Kuck’s method; (ii) synthesizing the
C1-symmetrical 2,6-dimethoxy-TBTQ derivative ( )-20 and
the C3-symmetrical 2,6,10-trimethoxy-TBTQ derivative ( )-21
based on Hopf’s method; (iii) examining the possibility of
resolving compounds ( )-18−( )-21 and closely related
hydroxy-/methoxy-substituted TBTQ derivatives ( )-22−
( )-25 by chiral HPLC; and (iv) determining the absolute
configurations of the resolvable enantiomers by X-ray
crystallography and/or circular dichorism (CD) spectroscopy.
Conceptually, the phenolic and methyl ether groups could be
conveniently transformed into the corresponding triflates,
which could then be subjected to various functional-group
conversions and C−C coupling reactions using transition-metal
catalysis. Therefore, these new findings open up a convenient
entry to a library of optically pure TBTQ molecules that could
required functional groups with respect to the precursor
molecule 26 before execution of this key double cyclization
reaction should enable one to control both the number and
positions of the introduced functionalities. In principle, C1-
symmetrical 2,6-disubstituted TBTQ derivatives ( )-27 could
be prepared from the corresponding precursors 26 having the
functionalities X located at the para position of one of the
phenyl rings and at the meta position of the other. Whereas
cyclization involving the meta-substituted phenyl ring can
incorporate the substituent X at either one of the inner or one
of the outer arene positions of the emerging TBTQ framework,
cyclization of the para-substituted ring introduces X exclusively
at one of the outer positions. However, because of the repulsive
interaction with the bridgehead hydrogen and the opposite
benzene ring, incorporation of the substituent at one of the
inner positions should be disfavored. As a result, the major
product of the two-fold cyclization reaction should be the C1-
symmetrical, 2,6-disubstituted TBTQ derivative ( )-27.
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Scheme 2. Regiocontrolled Synthesis of Racemic C1-Symmetrical 2,6-Disubstituted TBTQ Derivatives
Scheme 3. Possible Double Cyclization Strategy toward the 2,6,10- ( )-36 and 2,6,11- ( )-37 Trisubstituted TBTQ Skeletons
This idea was then executed by treatment of commercially
available 3-bromoanisole 28 with 1.1 equiv of n-butyllithium
followed by quenching with 4-methoxybenzaldehyde 29 to
afford the known diarylmethanol 3025 in 85% yield (Scheme 2).
Reaction of compound 30 and 2-methyl-1,3-indanedione in the
presence of para-toluenesulfonic acid in refluxing toluene gave
the coupling product 31 in 87% yield as a solid. The diketone
31 was then reduced to a diasteromeric mixture of diols 32 in
90% yield using lithium aluminum hydride. The mixture was
then subjected to acid-catalyzed double cyclization with
phosphoric acid to give the TBTQ derivative ( )-33 in 18%
yield. Although the presence of the electron-donating methoxy
group should stabilize the cationic intermediates, the cyclization
yield was slightly inferior to that (33%) of the reaction of the
unsubstituted precursor ( )-26 (X = H).11,24 Incidentally, the
1H and 13C NMR spectra showed only the presence of isomer
( )-33 in the isolated product. Hence, this method is clearly
superior to the direct introduction of suitable electrophiles into
the parent compound.
Compound ( )-33 was then converted to the corresponding
triallyl derivative ( )-34 using the sequence of reactions
reported before.9 Hence, reaction of ( )-33 with 4.0 equiv of
N-bromosuccinimide (NBS) gave the crude bridgehead-
substituted tribromide, which was not purified and was treated
with allyltrimethylsilane in the presence of tin tetrachloride to
give the triallyl derivative ( )-34 in 33% overall yield. Catalytic
hydrogenation of compound 34 in the presence of 10%
palladium on charcoal in ethyl acetate furnished the tri-n-propyl
TBTQ compound ( )-18 in 91% yield. The three alkyl groups
were essential to improve the solubility property of the TBTQ
compounds. Finally, the two methyl ether groups were cleaved
by boron tribromide to generate the 2,6-diphenol ( )-19 in
90% yield.
Although Kuck’s synthetic method allows the regioselective
synthesis of the C1-symmetrical ( )-2,6-disubstituted TBTQ
derivative ( )-18, the same strategy could find problems in the
synthesis of the C3-symmetrical 2,6,10-trisubstituted TBTQ
derivative ( )-36 (Scheme 3). By introducing an additional
methoxy group on the indane aromatic ring, there are now two
possible double cyclization modes for substrate 35. One
cyclization route should give the desired C3-symmetrical 2,6,10-
trisubstituted product ( )-36, but the other should generate
the C1-symmetrical 2,6,11-trisubstituted regioisomer ( )-37.
Knowing that Hopf’s method can afford much better
regiocontrol in producing the 2-substituted26 and C3-sym-
metrical TBTQ products,21 it was therefore decided to use
Hopf’s method to prepare the C1-symmetrical 2,6-dimethoxy-
TBTQ derivative ( )-20 and the C3-symmetrical 2,6,10-
trimethoxy-TBTQ analogue ( )-21.
Regioselective Synthesis of the C1-Symmetrical 2,6-
Dimethoxy- and C3-Symmetrical 2,6,10-Trimethoxy-
TBTQ Derivatives ( )-20 and ( )-21, Respectively,
Using Hopf’s Method. Treatment of the known 1,3-diketone
3827 and benzaldehyde 39 in the presence of piperidine and
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Scheme 4. Synthesis of the C1-Symmetrical 2,6-Dimethoxy- and C3-Symmetrical 2,6,10-Trimethoxy-TBTQ Derivatives ( )-20
and ( )-21, Respectively, Using Hopf’s Method
Figure 5. Chiral HPLC chromatograms of compounds ( )-19, ( )-20, ( )-21, ( )-23, and ( )-24.
hexanoic acid in refluxing toluene afforded the condensation
product 40 as a yellow solid in 78% yield (Scheme 4). The
diketone 40 was reduced to a separable mixture of
diastereomeric diols 41 in 90% yield using sodium borohydride
in the presence of cerium(III) chloride. Practically, the
diastereomers 41 were not separated and were subjected to
cyclization in the presence of polyphosphoric acid (PPA) in
chlorobenzene at 130 °C to give the 2,6-dimethoxy-TBTQ
derivative ( )-20 in 6% yield after recrystallization from
toluene.
trimethoxy-TBTQ derivative ( )-21 in a dismal 1% yield
after recrystallization from toluene. The poor cyclization yield
involving substrates containing the electron-donating methoxy
group was also observed by Hopf and co-workers.21,26
Nonetheless, the facts that both target compounds ( )-20
and ( )-21 could be obtained in just three steps and that no
tedious chromatographic purification was required still render
this route the most straightforward approach to prepare the 2,6-
disubstituted and 2,6,10-trisubstituted TBTQ molecules
( )-20 and ( )-21.
The 2,6,10-trimethoxy congener ( )-21 was similarly
prepared by replacing benzaldehyde with 4-methoxybenzalde-
hyde 29. The condensation product 42 and the corresponding
diol 43 were obtained in yields of 77% and 87%, respectively.
However, the final cyclization reaction gave the desired
Structural Characterization. All synthesized compounds
were fully characterized by a combination of 1H and 13C NMR
spectroscopies and mass spectral analysis (see Supporting
Information for spectra). In all cases, the spectroscopic data
were fully consistent with the proposed structures. The purities
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Scheme 5. Synthesis of the 2-Iodo-3-methoxy-TBTQ Derivative (M)-(−)-44 from (P)-(+)-23
Figure 6. X-ray crystal structures of (left) (M)-(−)-44 and (right) (P)-(+)-44, as obtained from hexane/CHCl3, with one molecule of CHCl3 per
molecule of 44 (30% thermal ellipsoids).
1
of the compounds were also confirmed by examining the H
NMR spectra. For example, only two methoxy signals were
found for the C1-symmetrical 2,6-dimethoxy compounds
( )-18, ( )-20, and ( )-33, and only one methoxy signal
contains bridgehead substituents, whereas the other (group II)
does not. It was found that the hydroxy-substituted TBTQ
derivatives in group I could be resolved, but the methoxy-
substituted analogues were not separable. In contrast, the
reverse was true for the group II derivatives: Only methoxy-
substituted TBTQ derivatives in group II could be resolved,
whereas the corresponding hydroxy-substituted analogues were
not separable. It is not known whether this observation is just a
coincidence or is due to some intriguing structural factors that
we are unable to identify at this moment.
1
was observed in the H NMR spectrum of the C3-symmetrical
2,6,10-trimethoxy compound ( )-21. In the case of the C1-
symmetrical compounds, the 18 carbon atoms of the three
aromatic rings were all chemically different, but because of their
very similar structural environments, partial signal overlapping
in the 13C NMR spectrum was noted. In contrast, the 13C NMR
spectrum of the C3-symmetrical compound ( )-21 was greatly
simplified and was found to consist of nine signals, thus again
confirming its C3 symmetry.
Optical Resolution. Scant systematic study on the optical
resolution of TBTQ derivatives is available in the literature.
This is partly due to the previous lack of convenient
regioselective synthetic routes to these molecules. Given that
we have now secured methods for the preparation of the 2,6-
dihydroxy-/dimethoxy-TBTQ derivatives ( )-18−( )-20 and
the 2,6,10-trimethoxy-TBTQ derivative ( )-21, we decided to
extend the optical resolution study to other known or readily
prepared 2-hydroxy-/methoxy-TBTQ analogues such as
( )-22,28 ( )-23,29 ( )-24,26 and ( )-25.26
All of these hydroxy-/methoxy-substituted TBTQ com-
pounds were thus subjected to chiral HPLC analysis using a
CHIRALPAK IB semipreparative column (20 mm × 250 mm)
with a solvent mixture of hexane and 2-propanol in different
ratios. Five compounds, namely, ( )-19, ( )-20, ( )-21,
( )-23, and ( )-24, were readily separable, whereas the
remaining three were not (Figure 5). These eight compounds
could be divided into two groups. One group (group I)
Determination of Absolute Configurations. The
absolute configurations of the separated enantiomers were
determined by circular dichroism (CD) spectroscopy and/or X-
ray crystallography by introducing a heavy-atom scatterer into
compound 23. Hence, the (+)-23 enantiomer, later identified
to have the (P) absolute configuration, was converted into the
corresponding methoxy derivative (P)-(+)-22 in 95% yield by
O-methylation (Scheme 5). The methoxy derivative (P)-(+)-22
was then treated with iodine in the presence of silver(II) sulfate
to give the 2-iodo-3-methoxy-TBTQ derivative (M)-(−)-44 in
87% yield. Likewise, the (M)-(−)-23 enantiomer was similarly
converted into (P)-(+)-44. Both enantiomers of 44 were
subjected to X-ray crystallographic analysis,30 and thus, their
absolute configurations were unambiguously established
(Figure 6).
Unfortunately, similar iodination or bromination of other
optically resolved TBTQ derivatives failed to produce crystals
suitable for X-ray analysis. We therefore resorted to using
circular dichorism (CD) spectroscopy to assign their absolute
configurations. As the absolute configurations of the two
enantiomers of 23 had already been confirmed, these
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Figure 7. (a) Structure of cyclotribenzylenes 45 and (b,c) CD profiles of the (b) B2u and (c) B1u transitions of cyclotrianisylene derivative (P)-46.
Figure 8. CD spectra (CH2Cl2, concentration = 1.5 mg/mL; path length = 1 mm) of the optically pure hydroxyl-/methoxy-substituted TBTQ
derivatives 19−21, 23, and 24.
enantiomers also served as testing cases to further validate the
exciton model of C3-symmetrical molecules derived from
cyclotribenzylene (CTB) proposed by Collet and co-work-
ers.31−33 Although some of our TBTQ molecules do not exhibit
C3 symmetry, the model, being based on the exciton coupling
between transition moments of the three aromatic chromo-
phores, should be applicable to the rigid TBTQ alicyclic-
aromatic skeleton that also falls into this structural category.34 It
should be noted that the exciton model was previously
validated by checking with CTB derivatives of known absolute
configuration.32,35
7).32,33 Two key transitions, namely, B2u and B1u, located at
approximately 290 and 240 nm, respectively, were identified in
the CD spectra. The sign of each CD couplet was determined
by the angle of rotation (defined as θ1 for B2u and θ2 for B1u in
Figure 7) of the transition moment of B2u and B1u, which, in
turn, was dependent on the relative magnitude of the
spectroscopic moments of the substituents (OMe and H)
and, hence, on the absolute configuration of the molecule. As
the spectroscopic moment of H is known to be less than that of
OMe and the angle of rotation (θ1) of the transition moment
(double-ended arrow in Figure 7b) responsible for the B2u
transition is known to fall in the range between 0° and −45°
(actual value is about −38°),32 the B2u couplet generates a
negative exciton pattern as shown in Figure 7b. For the B1u
The CD profiles of optically active C3-symmetric CTB 45 (X
≠ Y), especially that of the cyclotrianisylene derivative (P)-46,
were thoroughly analyzed by Collet and co-workers (Figure
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electrospray ionization (ESI), as indicated. Accurate mass measure-
ments were obtained on a mass spectrometer with a magnetic-sector-
type mass analyzer. Single-crystal X-ray diffraction measurements were
conducted on a CCD diffractometer using Mo Kα radiation. CD
spectra were recorded with a spectropolarimeter. UV measurements
were carried out using a UV−vis spectrophotometer. Specific rotations
were measured on a polarimeter. Chiral HPLC was conducted on a
CHIRALPAK IB column (20 mm × 250 mm) using an HPLC pump
equipped with a UV/visible detector. For each chromatographic run, 2
mL of the racemate sample at a concentration of 10−20 mg/mL was
injected into the column. The recovery yield of the separation process
was about 90−95%, and the absolute amount of pure enantiomers
isolated ranged from 9 to 18 mg per run.
Synthetic Procedures. (3-Methoxyphenyl)-(4-methoxyphenyl)-
methanol (30).25 n-BuLi (68.8 mL, 1.6 M in hexane, 110 mmol) was
added to a solution of 3-bromoanisole (18.7 g, 100 mmol) in THF
(100 mL) at −78 °C. After 1 h, 4-methoxybenzaldehyde (13.6 g, 100
mmol) in dry THF (10 mL) was added dropwise. After the addition,
the reaction mixture was allowed to warm to 25 °C over a period of 2
h. The mixture was then poured into ice water and extracted with
ether (3 × 100 mL). The combined extracts were dried (MgSO4),
filtered, and evaporated in vacuo. The residue was purified by column
chromatography (hexane/ethyl acetate = 5/1, Rf = 0.2) to give the
product 30 as a yellow oil (20.8 g, 85 mmol, 85%). 1H NMR (CDCl3):
δ 7.32−7.28 (m, 2H), 6.99−6.96 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H),
6.86−6.83 (m, 2H), 5.73 (d, J = 3 Hz, 1H), 3.804 (s, 3H), 3.800 (s,
3H), 2.96 (br s, 1H).
transition, the transition moment is similarly known to have an
angle of rotation (θ2) of −38°. In this case, the CD profile again
produces a negative exciton pattern as shown in Figure 7c. It
should be noted that the CD profile is inverted for the (M)-
enantiomer.
Examination of the CD profile of the (−)-enantiomer of the
C3-symmetric 2,6,10-trimethoxy-TBTQ derivative 21 identified
two negative exciton patterns centered at around 293 nm (B2u)
and 242 nm (B1u) (Figure 8c, yellow line). This spectral pattern
matches perfectly well to that of (P)-46, and hence, (−)-21
must exhibit a (P)-absolute configuration.
In the case of 2-hydroxy-TBTQ derivative 23, it is already
known from X-ray crystallography that the (+)-enantiomer
exhibits the (P)-absolute configuration. It turns out that the
spectroscopic moment of the hydroxy group is similar to that of
the methoxy group.32 As a result, the CD profile of the (P)-
enantiomer of the 2-hydroxy-TBTQ derivative 23 should be
similar to that shown in Figure 7b,c. Examination of Figure 8d
shows that the (+)-23 enantiomer gave rise to a negative
exciton pattern (brown line) due to the B1u transition centered
at 245 nm, whereas the exciton pattern due to the B2u transition
at 280 nm was too weak to be identified, possibly due to the
presence of just one chirally modified aromatic ring in the
system. Nonetheless, this result confirms that the enantiomer
(+)-23 exhibits a (P)-absolute configuration, which is
consistent with the X-ray data. Based on similar arguments, it
was concluded that the 2-methoxy analogue (+)-24 (Figure 8e,
brown line) also has a (P)-absolute configuration. For the 2,6-
dihydroxy 19 and 2,6-dimethoxy 20 analogues, the B2u
transition at 294 nm could be clearly identified. In both
cases, (−)-19 (Figure 8a, yellow line) and (−)-20 (Figure 8b,
yellow line) could be assigned to have a (P)-configuration.
Hence, the absolute configurations of (−)-19, (−)-20, (−)-21,
(−)-23, and (−)-24 are (P), (P), (P), (M), and (M),
respectively.
2-[(3-Methoxyphenyl)-(4-methoxyphenyl)methyl]-2-methyl-1H-
indene-1,3(2H)-dione (31). A mixture of 2-methyl-1,3-indanedione
(13.6 g, 85 mmol), diarylmethanol 30 (20.8 g, 85 mmol), and p-
toluenesulfonic acid monohydrate (0.81 g, 4.3 mmol) in toluene (100
mL) was heated at 110 °C for 24 h. The mixture was cooled to 25 °C,
washed with saturated K2CO3 solution, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane/ethyl acetate = 4/1, R = 0.2) to give the
f
product 31 as a colorless solid (28.6 g, 74 mmol, 87%); mp 109−110
1
°C. H NMR (CDCl3): δ 7.83−7.81 (m, 2H), 7.70−7.68 (m, 2H),
7.37 (d, J = 8.8 Hz, 2H), 7.08−7.00 (m, 3H), 6.69 (d, J = 8.8 Hz, 2H),
6.62 (dd, J = 7.6, 1.2 Hz, 1H), 4.51 (s, 1H), 3.72 (s, 3H), 3.68 (s, 3H),
1.29 (s, 3H). 13C NMR (CDCl3): δ 204.3, 159.3, 158.3, 141.7, 141.4,
135.6, 131.8, 130.7, 129.3, 123.1, 122.0, 115.1, 113.6, 112.4, 58.2, 57.0,
55.0, 20.0. MS (ESI) m/z (%): 409 (100, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C25H22O4 + Na]+, 409.1410;
found, 409.1416.
CONCLUSIONS
■
The C1-symmetrical 2,6-dihydroxy-/dimethoxy-TBTQ deriva-
tives ( )-18, ( )-19, and ( )-20 and the C3-symmetrical
2,6,10-trimethoxy-TBTQ derivative ( )-21 were synthesized in
a highly regioselective manner using either Kuck’s or Hopf’s
synthetic protocol. A systematic optical resolution study of a
series of 2-hydroxy-/methoxy-, 2,6-dihydroxy-/dimethoxy-, and
2,6,10-trimethoxy-TBTQ derivatives was conducted. The
absolute configurations of the separated enantiomers were
determined by X-ray crystallography and/or circular dichorism
spectroscopy. These optically pure 2,6-disubsituted and 2,6,10-
trisubstituted compounds are potentially interesting building
blocks for the construction of molecular squares and cubes.
2-[(3-Methoxyphenyl)-(4-methoxyphenyl)methyl]-2-methyl-2,3-
dihydro-1H-indene-1,3-diol (32). A solution of the diketone 31 (28.6
g, 74 mmol) in anhydrous THF (130 mL) was added dropwise to a
stirred suspension of LiAlH4 (4.5 g, 118 mmol) in dry THF (20 mL)
at 0 °C. After the addition was finished, the mixture was heated to
reflux for 12 h. The reaction was quenched by the addition of a small
amount of cool water, and the resulting suspension was filtered. The
filtrate was concentrated in vacuo, and the residue purified by silica gel
chromatography (hexane/ethyl acetate = 2/1, Rf = 0.2) to afford a
diastereomeric mixture of product 32 as a pale yellow solid (26.0 g, 67
1
mmol, 90%); mp 183−184 °C. H NMR (CDCl3): δ 7.49 (d, J = 8.8
Hz, 2H), 7.45−7.43 (m, 2H), 7.36−7.33 (m, 2H), 7.31−7.27 (m, 1H),
7.16−7.13 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.80 (dd, J = 8.0, 2.0 Hz,
1H), 5.16 (s, 1H), 4.60 (d, J = 7.2 Hz, 1H), 4.52 (d, J = 7.6 Hz, 1H),
3.811 (s, 3H), 3.809 (s, 3H), 2.26−2.23 (m, 2H), 0.84 (s, 3H). 13C
NMR (CDCl3): δ 159.8, 158.3, 144.91, 144.87, 144.0, 133.8, 131.0,
129.6, 129.3, 126.3, 122.4, 116.2, 114.0, 111.4, 81.93, 81.88, 55.33,
55.29, 53.6, 48.1, 20.6. MS (ESI) m/z (%): 413 (100, [M + Na]+).
Accurate mass measurement (ESI) m/z: calcd for [C25H26O4 + Na]+,
413.1723; found, 413.1726.
( )-2,6-Dimethoxy-12d-methyltribenzotriquinacene [( )-33]. A
solution of the diol 32 (26.0 g, 67 mmol) in xylenes (200 mL) was
dropped slowly into 85% orthophosphoric acid (15.6 mL, 254 mmol)
at 130 °C with vigorous stirring. After the addition was complete, the
mixture was heated to reflux for 20 h. The reaction mixture was cooled
to 25 °C and poured into water (100 mL). The organic layer was then
EXPERIMENTAL SECTION
■
General Information. All reactions that required anhydrous
conditions were carried out using standard procedures under an Ar
atmosphere. Commercially available reagents were used as received
without further purification. Solvents were dried by distillation over
the appropriate drying reagents. Column chromatography was
performed through silica gel 60 (70−230 mesh) unless otherwise
stated. Melting points were determined on a melting point apparatus
and are uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a 400 MHz spectrometer. Chemical shift
values are given in ppm, and coupling constants (J) are in Hz. Residual
1
solvent signals in the H and 13C NMR spectra were used as the
internal reference (CDCl3: δH = 7.26, δC = 77.16 ppm). Mass spectra
were recorded using either electron-impact ionization (EI) or
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washed with saturated aqueous NaHCO3 solution, dried (MgSO4),
filtered, and concentrated in vacuo to give an oil that was purified by
column chromatography (hexane/ethyl acetate = 10/1, Rf = 0.2) to
afford the product ( )- 33 as a gummy oil (4.3 g, 12 mmol, 18%). 1H
NMR (CDCl3): δ 7.43−7.39 (m, 2H), 7.33−7.30 (m, 2H), 7.20−7.18
(m, 2H), 6.96 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.77−6.73
(m, 2H), 4.41 (s, 1H), 4.39 (s, 1H), 4.36 (s, 1H), 3.78 (s, 3H), 3.77 (s,
3H), 1.67 (s, 3H). 13C NMR (CDCl3): δ 159.4, 158.4, 141.7, 141.5,
135.6, 131.9, 130.8, 129.4, 123.19, 123.17, 122.1, 115.2, 113.7, 112.5,
58.3, 57.1, 55.2, 20.1. MS (ESI) m/z (%): 354 (100, M•+). Accurate
mass measurement (ESI) m/z: calcd for C25H22O2•+, 354.1614; found,
354.1620.
( )-4b,8b,12b-Triallyl-2,6-dimethoxy-12d-methyltribenzotriqui-
nacene [( )-34]. A mixture of ( )-33 (1.0 g, 2.82 mmol), benzoyl
peroxide (0.11 g, 0.45 mmol), and NBS (2.0 g, 11.28 mmol) was
heated to reflux in CHCl3 (100 mL) under the irradiation of an
infrared lamp (245 W) for 5 h. After being allowed to cool to 25 °C,
the mixture was washed with saturated aqueous Na2S2O3 solution
followed by saturated aqueous NaHCO3 solution. The organic layer
was dried (MgSO4), filtered, and concentrated in vacuo to give the
corresponding tribromide as a yellow solid. The crude product was
then dissolved in anhydrous CH2Cl2 (50 mL) at 0 °C, and tin
tetrachloride (1.3 mL, 11.28 mmol) and allyltrimethylsilane (1.8 mL,
11.28 mmol) were slowly added in sequence. The mixture was stirred
at 25 °C for 24 h, and the reaction was quenched with water. The
inorganic salts were filtered off, and the filtrate was extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo, and the residue was purified by
column chromatography (hexane/ethyl acetate = 30/1, Rf = 0.2) to
give compound ( )-34 as a colorless solid (0.44 g, 0.93 mmol, 33%);
mp 151−152 °C. 1H NMR (400 MHz): δ 7.33−7.28 (m, 2H), 7.23−
7.15 (m, 4H), 6.84 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.76−
6.72 (m, 2 H), 5.65−5.53 (m, 3H), 5.11−5.07 (m, 3H), 4.97−4.95 (m,
3H), 3.76 (s, 3H), 3.75 (s, 3H), 3.01−2.98 (m, 6H), 1.66 (s, 3H). 13C
NMR (CDCl3): δ 159.6, 149.3, 149.1, 148.1, 147.3, 140.0, 139.9,
137.42, 137.37, 137.3, 127.7, 127.5, 124.1, 123.5, 123.4, 116.5, 116.40,
116.36, 113.7, 113.5, 108.7, 108.6, 74.0, 66.1, 65.6, 65.5, 55.5, 42.8,
42.6, 17.3. MS (ESI) m/z (%): 497 (100, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C34H34O2 + Na]+, 497.2451;
found, 497.2450.
( )-2,6-Dimethoxy-12d-methyl-4b,8b,12b-tri-n-propyltribenzotri-
quinacene [( )-18]. A mixture of triallyltribenzotriquinance 34 (0.44
g, 0.93 mmol), 10% palladium-on-charcoal (0.15 g, 10%), and
anhydrous ethyl acetate (20 mL) was stirred at 25 °C under a
hydrogen atmosphere (1 atm) for 24 h. The catalyst was removed by
filtration through a short pad of silica gel. The solvent was
concentrated in vacuo, and the residue was purified by silica gel
chromatography (hexane/ethyl acetate = 30/1, Rf = 0.2) to afford the
tripropyl TBTQ ( )-18 as a colorless solid (0.41 g, 0.85 mmol, 91%);
mp 184−185 °C. 1H NMR (CDCl3): δ 7.28−7.24 (m, 2H), 7.17 (dd, J
= 8.4, 3.2 Hz, 2H), 7.12−7.10 (m, 2H), 6.81 (d, J = 1.6 Hz, 1H), 6.76
(d, J = 2 Hz, 1H), 6.71−6.68 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H),
2.14−2.08 (m, 6H), 1.59 (s, 3H), 1.20−1.10 (m, 6H), 0.95−0.85 (m,
9H). 13C NMR (CDCl3): δ 159.33, 159.29, 149.8, 149.6, 148.6, 147.8,
140.6, 140.5, 127.3, 127.1, 124.0, 123.9, 123.4, 123.3, 113.2, 113.1,
108.7, 108.5, 72.7, 67.2, 66.6, 66.5, 55.4, 41.1, 41.0, 40.9, 20.61, 20.55,
15.4, 15.3. MS (ESI) m/z (%): 503 (100, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C34H40O2 + Na]+, 503.2921;
found, 503.2924.
( )-2,6-Dihydroxy-12d-methyl-4b,8b,12b-tri-n-propyltribenzotri-
quinacene [( )-19]. Boron tribromide (1.9 mL, 1.87 mmoL) was
added slowly to a solution of dimethoxy-TBTQ ( )-18 (0.41 g, 0.85
mmol) in anhydrous CH2Cl2 (15 mL) at 0 °C. The mixture was
stirred at 20 °C for 12 h. The reaction was quenched with water, and
the mixture was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo, and the residue was purified by column chromatography
(hexane/ethyl acetate = 1/1, R f = 0.3) to obtain ( )-19 as a colorless
solid (0.35 g, 0.77 mmol, 90%); mp >252 °C (dec). 1H NMR
(CDCl3): δ 7.25−7.22 (m, 2H), 7.13−7.05 (m, 4H), 6.73 (d, J = 2.0
Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.60−6.55 (m, 2H), 4.91 (s, 2H),
2.10−2.04 (m, 6H), 1.58 (s, 3H), 1.22−1.17 (m, 6H), 0.92−0.89 (m,
9H). 13C NMR (CDCl3): δ 155.12, 155.08, 150.2, 150.0, 148.6, 147.8,
140.6, 140.4, 127.3, 127.1, 124.2, 124.1, 123.44, 123.37, 114.92,
114.87, 109.8, 109.7, 72.8, 67.1, 66.6, 66.5, 64.8, 41.2, 40.9, 40.8, 25.4,
20.6, 20.5, 15.34, 15.27. MS (ESI) m/z (%): 475 (100, [M + Na]+).
Accurate mass measurement (ESI) m/z: calcd for [C32H36O2 + Na]+,
475.2608; found, 475.2610.
(P)-(−)-19: Colorless solid; mp >252 °C (dec); [α]2D0 = −75.8 (c =
1
0.4, CH2Cl2). H NMR (CDCl3): δ 7.25−7.23 (m, 2H), 7.13−7.10
(m, 3H), 7.03−6.97 (m, 1H), 6.72 (s, 1H), 6.68 (d, J = 2.4 Hz, 1H),
6.59 (dd, J = 8.4, 2.0 Hz, 1H), 6.48−6.40 (m, 1H), 4.66 (br s, 1H),
4.57 (br s, 1H), 2.15−2.00 (m, 6H), 1.60 (s, 3H), 1.25−1.10 (m, 6H),
0.95−0.80 (m, 9 H). 13C NMR (CDCl3): δ 155.1, 155.0, 150.2, 150.0,
148.6, 147.8, 140.7, 140.5, 127.4, 127.1, 124.22, 124.16, 123.45,
123.38, 114.94, 114.88, 109.8, 109.6, 72.8, 67.1, 66.6, 66.5, 41.1, 40.90,
40.86, 20.6, 20.5, 15.4, 15.30, 15.28. MS (ESI) m/z (%): 475 (100, [M
+ Na]+). Accurate mass measurement (ESI) m/z: calcd for [C32H36O2
+ Na]+, 475.2608; found, 475.2615.
(M)-(+)-19: Colorless solid; mp >252 °C (dec); [α]2D0 = +76.4 (c =
1
0.4, CH2Cl2). H NMR (CDCl3): δ 7.26−7.22 (m, 2H), 7.12−7.10
(m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.68 (d, J
= 2.4 Hz, 1H), 6.60−6.51 (m, 2H), 4.61 (br s, 1H), 4.57 (br s, 1H),
2.11−2.03 (m, 6H), 1.58 (s, 3H), 1.22−1.13 (m, 6H), 0.93−0.89 (m,
9H). 13C NMR (CDCl3): δ 155.1, 155.0, 150.2, 150.0, 148.6, 147.8,
140.7, 140.6, 127.4, 127.1, 124.23, 124.17, 123.45, 123.37, 115.0,
114.9, 109.8, 109.6, 72.8, 67.1, 66.6, 66.5, 41.1, 40.90, 40.87, 20.6, 20.5,
15.4, 15.30, 15.28. MS (ESI) m/z (%): 475 (100, [M + Na]+).
Accurate mass measurement (ESI) m/z: calcd for [C32H36O2 + Na]+,
475.2608; found, 475.2610.
2-Benzylidene-1,3-bis(4-methoxyphenyl)propane-1,3-dione (40).
A mixture of 1,3-bis(4-methoxyphenyl)propane-1,3-dione (20.0 g, 70
mmol) 38,27 benzaldehyde 39 (8.2 g, 77 mmol), piperidine (0.9 mL,
9.1 mmol), and hexanoic acid (2.2 mL, 17.5 mmol) in toluene (200
mL) was heated to reflux using a Dean−Stark trap for 20 h. The
mixture was cooled to 25 °C; and washed sequentially with saturated
aqueous NaHCO3 solution, 5% aqueous acetic acid solution, aqueous
K2CO3 solution, and brine; and dried (MgSO4). The organic solvent
was filtered and concentrated in vacuo, and the residue was
recrystallized from methanol to give the product 40 as a yellow
solid (20.3 g, 54.6 mmol, 78%); mp 128−129 °C. 1H NMR (CDCl 3):
δ 7.97 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H),
7.37−7.35 (m, 2H), 7.29−7.22 (m, 3H), 6.96 (d, J = 8.4 Hz, 2H), 6.87
(d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.82 (s, 3H). 13C NMR (CDCl3): δ
195.3, 193.3, 164.1, 163.4, 141.6, 140.2, 133.4, 132.1, 131.9, 130.0,
129.9, 129.6, 128.7, 114.1, 113.8, 55.5, 55.4. MS (ESI) m/z (%): 395
(100, [M + Na]+). Accurate mass measurement (ESI) m/z: calcd for
[C24H20O4 + Na]+, 395.1254; found, 395.1268.
2-Benzylidene-1,3-bis(4-methoxyphenyl)propane-1,3-diol (41). A
solution of the diketone 40 (10.0 g, 26.9 mmol) was dissolved in
CH2Cl2 (150 mL) and stirred at −78 °C under nitrogen. A methanolic
solution (150 mL) of cerium chloride heptahydrate (21.0 g, 56.5
mmol) was then added, followed by sodium borohydride (3.1 g, 80.7
mmol) in small batches. The mixture was kept at −78 °C for 1 h and
then allowed to warm to 25 °C over a period of 2 h. The reaction was
quenched with 1.0 M hydrochloride acid, and the mixture was
extracted with ether (3 × 100 mL). The organic extracts were
combined, dried (MgSO4), filtered, and concentrated under reduced
pressure to give a residue that was purified by silica gel
chromatography (hexane/CH2Cl2/ethyl acetate = 5/3/1, Rf = 0.2
and 0.1) to afford two diastereomers of 41. Faster-running
diastereomer: Colorless solid (3.75 g, 10.0 mmol, 37%); mp 97.0−
97.5 °C. 1H NMR (CDCl3): δ 7.34−7.25 (m, 9H), 7.04 (s, 1H), 6.89
(d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.89 (d, J = 6.4 Hz, 1H),
5.32 (d, J = 2.8 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.00−1.95 (m,
2H). 13C NMR (CDCl3): δ 159.4, 158.8, 143.9, 136.5, 135.2, 134.6,
129.6, 128.9, 128.6, 128.5, 127.4, 127.2, 114.2, 113.8, 73.7, 71.0, 55.40,
55.38. MS (ESI) m/z (%): 399 (100, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C24H24O4+Na]+, 399.1567; found,
399.1572. Slower-running diastereomer: Colorless solid (5.4 g, 14.3
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1
mmol, 53%); mp 126.5−127.0 °C. H NMR (CDCl3): δ 7.32−7.22
diastereomers, which was separated by silica gel chromatography
(m, 7H), 7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.85 (d, J
= 8.8 Hz, 2H), 6.22 (s, 1H), 5.91 (d, J = 6.8 Hz, 1H), 5.28 (d, J = 2.8
Hz, 1H), 4.14 (d, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.34 (d, J
= 3.2 Hz, 1H). 13C NMR (CDCl3): δ 159.1, 158.7, 144.0, 136.4, 134.8,
133.7, 132.4, 128.8, 128.4, 127.4, 126.9, 113.8, 113.7, 74.4, 71.8, 55.37,
55.35. MS (ESI) m/z (%): 399 (100, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C24H24O4 + Na]+, 399.1567;
found, 399.1570.
( )-2,6-Dimethoxytribenzotriquinacene [( )-(20)]. A mixture of
the diol 41 (3.0 g, 8.0 mmol) and polyphosphoric acid (1.5 g) in
chlorobenzene (21 mL) was stirred vigorously at 130 °C. The mixture
was cooled to 25 °C, and the solvent was concentrated in vacuo. The
residue was chromatographed on silica gel (hexane/ethyl acetate = 20/
1, Rf = 0.2) to afford a pale yellow solid that was recrystallized from
toluene to yield the product ( )-20 as a colorless solid (0.16 g, 0.48
(hexane/CH2Cl2/ethyl acetate = 5/4/1, Rf = 0.2 and 0.1). Faster-
1
running diastereomer: Colorless oil (3.0 g, 30%). H NMR (CDCl3):
δ 7.30−7.26 (m, 6H), 6.94 (s, 1H), 6.89−6.84 (m, 6H); 5.89 (s, 1H),
5.31 (s, 1H), 3.81 (s, 6H), 3.80 (s, 3H), 2.07 (br s, 2H). 13C NMR
(CDCl3): δ 159.5, 159.0, 158.8, 142.4, 135.3, 134.7, 130.3, 129.3,
128.9, 128.7, 127.3, 114.2, 113.9, 113.8, 73.9, 71.2, 55.44, 55.41. MS
(ESI) m/z (%): 429 (100, [M + Na]+). Accurate mass measurement
(ESI) m/z: calcd for [C25H26O5 + Na]+, 429.1672; found, 429.1679.
1
Slower-running diastereomer: Colorless oil (5.7 g, 57%). H NMR
(CDCl3): δ 7.35 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.20 (d,
J = 9 Hz, 2H), 6.92−6.83 (m, 6H), 6.16 (s, 1H), 5.95 (d, J = 7.6 Hz,
1H), 5.30 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (d, J =
7.6 Hz, 1H), 2.67 (d, J = 2.8 Hz, 1H). 13C NMR (CDCl3): δ 159.1,
159.0, 158.7, 142.7, 134.9, 133.9, 132.0, 130.2, 128.8, 128.4, 126.9,
113.82, 113.80, 113.7, 74.5, 71.9, 55.38, 55.36, 55.3. MS (ESI) m/z
(%): 429 (100, [M + Na]+). Accurate mass measurement (ESI) m/z:
calcd for [C25H26O5 + Na]+, 429.1672; found, 429.1677.
1
mmol, 6%); mp >209 °C (dec). H NMR (CDCl3): δ 7.45−7.41 (m,
2H), 7.34 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.19−7.17 (m,
2H), 6.99 (s, 1H), 6.94 (s, 1H), 6.76−6.73 (m, 2H), 4.91−4.84 (m,
3H), 4.55 (q, J = 9.6 Hz, 1H), 3.783 (s, 3H), 3.776 (s, 3H). 13C NMR
(CDCl3): δ 159.7, 159.6, 147.7, 147.5, 146.4, 145.5, 138.1, 138.0,
127.5, 127.4, 124.9, 124.8, 124.39, 124.36, 113.5, 113.4, 109.7, 109.6,
56.0, 55.6, 55.21, 55.15, 52.6. MS (ESI) m/z (%): 363 (100, [M +
Na]+). Accurate mass measurement (ESI) m/z: calcd for [C24H20O2 +
Na]+, 363.1356; found, 363.1352.
2,6,10-Trimethoxytribenzotriquinacene [( )-(21)]. The prepara-
tion procedure was similar to that used for ( )-20. Starting from diol
43 (3.0 g, 7.4 mmol), the product ( )-21 was obtained as a colorless
solid (27.1 mg, 72.9 μmmol, 1%) and separated by flash
chromatography (hexane/ethyl acetate = 10/1, Rf = 0.2); mp >205
°C (dec). 1H NMR (CDCl3): δ 7.33 (d, J = 8.4 Hz, 3H), 6.95 (s, 3H),
6.74 (d, J = 8.4 Hz, 3H), 4.82 (d, J = 9.6 Hz, 3H), 4.51 (q, J = 9.6 Hz,
1H), 3.78 (s, 9H). 13C NMR (CDCl3): δ 159.6, 147.8, 137.8, 124.8,
113.3, 109.6, 55.6, 55.1, 53.2. MS (ESI) m/z (%): 393 (100, [M +
Na]+). Accurate mass measurement (ESI) m/z: calcd for [C25H22O3 +
Na]+, 393.1461; found, 393.1466.
(M)-(+)-20: Colorless solid; mp >208 °C (dec); [α]2D0 = +144.3 (c
= 0.2, CH2Cl2). 1H NMR (CDCl3): δ 7.46−7.41 (m, 2H), 7.34 (d, J =
8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.19−7.17 (m, 2H), 6.99 (d, J = 2
Hz, 1H), 6.94 (d, J = 2 Hz, 1H), 6.76−6.73 (m, 2H), 4.91−4.84 (m,
3H), 4.55 (q, J = 9.6 Hz, 1H), 3.784 (s, 3H), 3.777 (s, 3H). 13C NMR
(CDCl3): δ 159.64, 159.61, 147.7, 147.5, 146.4, 145.5, 138.0, 127.6,
127.5, 124.8, 124.39, 124.36, 113.5, 113.4, 109.7, 109.6, 56.0, 55.6,
55.2, 55.1, 52.6. MS (ESI) m/z (%) 341 (45, [M + H]+). Accurate
mass measurement (ESI) m/z: calcd for [C24H20O2 + H]+, 341.1536;
found, 341.1527.
(M)-(+)-21: Colorless solid; mp >205 °C (dec); [α]2D0 = +147.8 (c
1
= 0.2, CH2Cl2). H NMR (CDCl3): δ 7.32 (d, J = 8.4 Hz, 3H), 6.94
(d, J = 1.2 Hz, 3H), 6.74 (dd, J = 8.4, 2.0 Hz, 3H), 4.83 (d, J = 9.6 Hz,
3H), 4.52 (q, J = 9.6 Hz, 1H), 3.78 (s, 9H). 13C NMR (CDCl3): δ
159.6, 147.9, 137.8, 124.9, 113.4, 109.7, 55.6, 55.2, 53.2. MS (ESI) m/z
(%): 393 (100, [M + Na]+). Accurate mass measurement (ESI) m/z:
calcd for [C25H22O3 + Na]+, 393.1461; found, 393.1462.
(P)-(−)-20: Colorless solid; mp >208 °C (dec); [α]2D0 = −148.1 (c
= 0.2, CH2Cl2). 1H NMR (CDCl3): δ 7.46−7.42 (m, 2H), 7.35 (d, J =
8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.20−7.18 (m, 2H), 7.0 (s, 1H),
6.95 (s, 1H), 6.77−6.73 (m, 2H), 4.91−4.84 (m, 3H), 4.55 (q, J = 9.6
Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H). 13C NMR (CDCl3): δ 159.62,
159.59, 147.7, 147.5, 146.4, 145.5, 138.04, 138.00, 127.5, 127.4, 124.9,
124.8, 124.38, 124.35, 113.5, 113.4, 109.7, 109.6, 55.9, 55.6, 55.2, 55.1,
52.6. MS (ESI) m/z (%): 341 (100, [M + H]+). Accurate mass
measurement (ESI) m/z: calcd for [C24H20O2 + H]+, 341.1536; found,
341.1533.
(P)-(−)-21: Colorless solid; mp >205 °C (dec); [α]2D0 = −136.5 (c
1
= 0.2, CH2Cl2). H NMR (CDCl3): δ 7.32 (d, J = 8.4 Hz, 3H), 6.94
(d, J = 1.6 Hz, 3H), 6.73 (dd, J = 8.0, 2.4 Hz, 3H), 4.83 (d, J = 9.6 Hz,
3H), 4.52 (q, J = 9.2 Hz, 1H), 3.77 (s, 9H). 13C NMR (CDCl3): δ
159.6, 147.9, 137.8, 124.9, 113.4, 109.7, 55.6, 55.2, 53.2. MS (ESI) m/z
(%): 371 (100, [M + H]+). Accurate mass measurement (ESI) m/z:
calcd for [C25H22O3 + H]+, 371.1642; found, 371.1646.
( )-2-Hydroxy-4b,8b,12b,12d-tetramethyltribenzotriquinacene
[( )-23]. Compound ( )-23 was synthesized according to a published
method.29
2-(4-Methoxybenzylidene)-1,3-bis(4-methoxyphenyl)propane-
1,3-dione (42). A mixture of 1,3-bis(4-methoxyphenyl)propane-1,3-
dione 3827 (20.0 g, 70 mmol), 4-methoxybenzaldehyde 29 (10.5 g, 77
mmol), piperidine (0.9 mL, 9.1 mmol), and hexanoic acid (2.2 mL,
17.5 mmol) in toluene (200 mL) was heated to reflux with a Dean−
Stark apparatus for 20 h under nitrogen. The mixture was cooled to 25
°C; washed sequentially with saturated aqueous NaHCO3 solution, 5%
aqueous acetic acid solution, aqueous K2CO3 solution, and brine; and
dried (MgSO4). The organic solvent was dried (MgSO4), filtered, and
concentrated in vacuo to give an oil that was chromatographed on
silica gel (hexane/ethyl acetate = 5/1, R f = 0.2) to afford the product
42 as a yellow oil (21.8 g, 54 mmol, 77%). 1H NMR (CDCl3): δ 7.97
(d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.32 (d, J =
8.8 Hz, 2H), 6.94 (d, J = 8 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 6.77 (d, J
= 8.8 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H). 13C NMR
(CDCl3): δ 195.9, 193.5, 164.0, 163.1, 161.1, 142.2, 137.6, 132.0,
131.9, 131.8, 130.2, 129.7, 125.8, 114.2, 114.0, 113.7, 55.42, 55.41,
55.2. MS (ESI) m/z (%): 425 (100, [M + Na]+). Accurate mass
(M)-(−)-23: Colorless solid; mp >250 °C (dec); [α]2D0 = −61.6 (c =
1
0.2, CH2Cl2). H NMR (CDCl3): δ 7.41−7.37 (m, 2H), 7.35−7.31
(m, 2H), 7.21−7.14 (m, 5H), 6.82 (d, J = 2.4 Hz, 1H), 6.62 (dd, J =
8.4, 2.4 Hz, 1H), 4.73 (br s, 1H), 1.68 (s, 3H), 1.65 (s, 6H), 1.36 (s,
3H). 13C NMR (CDCl3): δ 155.4, 150.7, 149.3, 149.1, 148.8, 148.7,
141.5, 127.8, 127.69, 127.66, 127.6, 123.8, 123.1, 123.03, 123.01,
122.9, 115.3, 109.5, 70.2, 62.8, 62.7, 62.2, 26.13, 26.08, 25.9, 16.3. MS
(ESI) m/z (%): 375 (100, [M + Na]+). Accurate mass measurement
(ESI) m/z: calcd for [C26H24O + Na]+, 375.1719; found, 375.1728.
(P)-(+)-23: Colorless solid; mp >250 °C (dec); [α]2D0 = +55.6 (c =
1
0.2, CH2Cl2). H NMR (CDCl3): δ 7.39−7.36 (m, 2H), 7.35−7.31
(m, 2H), 7.21−7.15 (m, 5H), 6.82 (d, J = 2.4 Hz, 1H), 6.62 (dd, J =
8.4, 2.4 Hz, 1H), 4.66 (br s, 1H), 1.67 (s, 3H), 1.65 (s, 6H), 1.36 (s,
3H). 13C NMR (CDCl3): δ 155.4, 150.7, 149.3, 149.1, 148.8, 148.7,
141.5, 127.8, 127.78, 127.7, 123.8, 123.1, 123.04, 123.01, 122.9, 115.3,
109.5, 70.2, 62.8, 62.6, 62.2, 26.14, 26.08, 25.9, 16.3. MS (ESI) m/z
(%): 375 (100, [M + Na]+). Accurate mass measurement (ESI) m/z:
calcd for [C26H24O + Na]+, 375.1719; found, 375.1718.
measurement (ESI) m/z: calcd for [C25H22O + Na]+, 425.1359;
5
( )-2-Methoxytribenzotriquinacene [( )-(24)]. This compound
was prepared according to the method described in the literature.26
(P)-(+)-24: Colorless solid; mp >213 °C (dec); [α]2D0 = +31.9 (c =
0.2, CH2Cl2). H NMR (CDCl3): δ 7.47−7.40 (m, 4H), 7.34 (d, J =
8.0 Hz, 1H), 7.19−7.16 (m, 4H), 6.98 (d, J = 2.0 Hz, 1H), 6.74 (dd, J
= 8.4, 2.0 Hz, 1H), 4.96−4.89 (m, 3H), 4.50 (q, J = 9.6 Hz, 1H), 3.78
found, 425.1359.
2-(4-Methoxybenzylidene)-1,3-bis(4-methoxyphenyl)propane-
1,3-diol (43). The preparation procedure was the same as that used for
compound 41. Starting from diketone 42 (10.0 g, 24.8 mmol), cerium
chloride heptahydrate (19.4 g, 52.1 mmol), and sodium borohydride
(2.8 g, 74.4 mmol), the product 43 was obtained as a mixture of two
1
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Article
(s, 3H). 13C NMR (CDCl3): δ 159.6, 147.4, 146.3, 146.1, 145.8, 145.7,
138.2, 127.6, 127.51, 127.49, 127.4, 124.9, 124.44, 124.40, 124.3,
113.5, 109.7, 56.0, 55.9, 55.6, 55.2, 51.9. MS (ESI) m/z (%): 333 (100,
[M + Na]+). Accurate mass measurement (ESI) m/z: calcd for
[C23H18O + Na]+, 333.1250; found, 333.1250.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra and mass spectra of all new
compounds; chiral HPLC conditions for the optical resolution
of compounds ( )-19, ( )-20, ( )-21, ( )-23, and ( )-24;
UV spectra of compounds ( )-19, ( )-20, ( )-21, ( )-23,
and ( )-24; and CIF files for compounds (P)-(+)-44·CHCl3
and (M)-(−)-44·CHCl3. This material is available free of
charge via the Internet at http://pubs.acs.org.
(M)-(−)-24: Colorless solid; mp >213 °C (dec); [α]2D0 = −44.1 (c =
1
0.2, CH2Cl2). H NMR (CDCl3): δ 7.48−7.41 (m, 4H), 7.35 (d, J =
8.4 Hz, 1H), 7.20−7.17 (m, 4H), 6.99 (d, J = 1.6 Hz, 1H), 6.75 (dd, J
= 8.0, 2.4 Hz, 1H), 4.97−4.90 (m, 3H), 4.50 (q, J = 9.6 Hz, 1H), 3.78
(s, 3H). 13C NMR (CDCl3): δ 159.6, 147.4, 146.3, 146.1, 145.8, 145.7,
138.2, 127.6, 127.51, 127.49, 127.4, 124.9, 124.44, 124.40, 124.3,
113.5, 109.7, 56.0, 55.9, 55.6, 55.2, 51.9. MS (ESI) m/z (%): 333 (100,
[M + Na]+). Accurate mass measurement (ESI) m/z: calcd for
[C23H18O + Na]+, 333.1250; found, 333.1250.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: hfchow@cuhk.edu.hk.
*E-mail: caoxplzu@163.com.
*E-mail: dietmar.kuck@uni-bielefeld.de.
■
(M)-(−)-2-Methoxy-4b,8b,12b,12d-tetramethyltribenzotriquina-
cene [(M)-(−)-22]. A mixture of (M)-(−)-23 (0.50 g, 1.42 mmol),
K2CO3 (0.39 g, 2.84 mmol), and methyl iodide (97 μL, 1.56 mmol)
was stirred in a sealed tube at 45 °C for 12 h. The inorganic salts were
filtered, and the filtrate were concentrated in vacuo. The residue was
purified by flash chromatography (hexane/ethyl acetate = 20/1, Rf =
0.2) to obtain the product (M)-(−)-22 as a colorless solid (0.49 g,
1.35 mmol, 95%); mp 236−237 °C; [α]2D0 = −64.8 (c = 0.4, CH2Cl2).
1H NMR (CDCl3): δ 7.42−7.35 (m, 4H), 7.29 (d, J = 8.4 Hz, 1H),
7.21−7.17 (m, 4H), 6.92 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.4, 2.4 Hz,
1H), 3.78 (s, 3H), 1.694 (s, 3H), 1.686 (s, 3H), 1.676 (s, 3H), 1.39 (s,
3H). 13C NMR (CDCl3): δ 159.7, 150.4, 149.3, 149.1, 148.8, 148.7,
141.5, 127.8, 127.7, 127.6, 123.6, 123.1, 123.0, 122.9, 113.6, 108.3,
70.2, 62.79, 62.75, 62.2, 55.6, 26.13, 26.06, 26.0, 16.3. MS (ESI) m/z
(%): 367 (100, [M + H]+). Accurate mass measurement (ESI) m/z:
calcd for [C27H26O + H]+, 367.2056; found, 367.2076.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the NSFC/RGC Joint Research
Scheme (Nos. 21061160494 and N_CUHK467/10), the
NSFC (No. 21272098) and the '111' Program of MOE for
financial support.
REFERENCES
■
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0.4, CH2Cl2). H NMR (CDCl3): δ 7.41−7.36 (m, 4H), 7.30 (d, J =
8.4 Hz, 1H), 7.21 −7.18 (m, 4H), 6.92 (s, 1H), 6.77 (dd, J = 8.4, 1.6
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mmol), silver sulfate (0.25 g, 0.81 mmol), and iodine (0.38 g, 1.49
mmol) in acetonitrile (10 mL) was stirred at 25 °C for 24 h. The
reaction with excess iodine was quenched with sodium thiosulfate, and
the precipitate was filtered. The filtrate was washed with saturated
NaHCO3 solution, dried (MgSO4), filtered, concentrated in vacuo,
and purified by flash chromatography (hexane/ethyl acetate = 20/1, Rf
= 0.2) to give (P)-(+)-44 as a colorless solid (0.58 g, 1.17 mmol,
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7.21−7.16 (m, 4H), 6.80 (s, 1H); 3.87 (s, 3H), 1.66 (s, 6H), 1.63 (s,
3H), 1.35 (s, 3H). 13C NMR (CDCl3): δ 157.9, 150.7, 149.1, 148.7,
148.6, 148.2, 143.4, 133.7, 128.0, 127.89, 127.83, 127.8, 123.2, 123.1,
122.9, 122.7, 105.4, 85.5, 70.3, 62.8, 62.7, 62.0, 56.7, 26.1, 26.0, 25.8,
16.3. MS (ESI) m/z (%): 515 (40, [M + Na]+). Accurate mass
measurement (ESI) m/z: calcd for [C27H25IO + Na]+, 515.0842;
found, 515.0860.
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(P)-(+)-44 but starting from (P)-(+)-22. Colorless solid; mp 223−225
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1
1H), 7.41−7.37 (m, 2H), 7.35−7.31 (m, 2H), 7.22−7.17 (m, 4H),
6.81 (s, 1H), 3.87 (s, 3H), 1.67 (s, 6H), 1.64 (s, 3H), 1.36 (s, 3H). 13C
NMR (CDCl3): δ 157.9, 150.7, 149.1, 148.7, 148.6, 148.2, 143.4,
133.7, 128.0, 127.9, 127.82, 127.78, 123.2, 123.1, 122.9, 122.7, 105.4,
85.5, 70.3, 62.8, 62.7, 62.0, 56.7, 26.1, 26.0, 25.8, 16.3. MS (ESI) m/z
(%): 510 (100, [M + NH4]+). Accurate mass measurement (ESI) m/z:
calcd for [C27H25IO + NH4]+, 510.1288; found, 510.1282.
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(30) X-ray crystal data for (P)-(+)-44·CHCl3 from chloroform/
hexane: C28H26Cl3IO; M = 611.74; orthorhombic; a = 14.7136(15) Å,
b = 6.2522(6) Å, c = 29.166(3) Å; α = 90.00°, β = 90.00°, γ = 90.00°;
V = 2683.1(5) Å3; space group P212121; Z = 4; ρcalcd = 1.514 Mg m−3;
T = 296(2) K; λ (Mo Kα) = 0.71073 Å; 22022 reflections collected;
4865 independent reflections; Rint = 0.0691; observed data with I ≥
2σ(I) = 4413; R1 = 0.0596, wR2 = 0.1716 [I ≥ 2σ(I)]. CCDC-
1014029 contains the supplementary crystallographic data for (P)-
(+)-44·CHCl3. X-ray crystal data for (M)-(−)-44·CHCl3 from
chloroform/hexane: C28H26Cl3IO; M = 611.74; orthorhombic; a =
6.2440(6) Å, b = 14.7133(14) Å, c = 29.145(3) Å; α = 90.00°, β =
90.00°, γ = 90.00°; V = 2677.5(4) Å3; space group P212121; Z = 4;
ρcalcd = 1.518 Mg m−3; iT = 296(2) K; λ (Mo Kα) = 0.71073 Å; 21795
reflections collected; 4842 independent reflections; Rint = 0.0652;
observed data with I ≥ 2σ(I) = 4377; R1 = 0.0586, wR2 = 0.1672 [I ≥
2σ(I)]. CCDC-1013944 contains the supplementary crystallographic
data for (M)-(−)-44·CHCl3.
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