Optically active calixarenes conduced by methylene substitution

Article abstract of DOI:10.1021/ja905990u

(Figure Presented) The first method for the synthesis of optically active calix[4]arenes that are chiral as a result of substitution on the methylene bridges is described. The key step in the synthesis involves the reaction of a biscarbene complex with a

Full text of DOI:10.1021/ja905990u

Published on Web 11/24/2009
Optically Active Calixarenes Conduced by Methylene Substitution
Vijay Gopalsamuthiram, Alexander V. Predeus, Rui H. Huang, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received July 24, 2009; E-mail: wulff@chemistry.msu.edu
Calixarenes have become one of the most popular scaffolds for
constructing receptors for supramolecular chemistry.1 In an effort
to extend the use of scaffolds to chiral recognition events, there
has been an interest in chiral calixarenes. The easiest approach is
to covalently attach a chiral molecule to either the upper rim
(benzene ring) or lower rim (oxygens) of the calixarene, and this
approach has been studied extensively. A much more difficult and
much less frequently encountered method is to generate a chiral
calixarene by controlling the substitution pattern of the different
benzene rings in the calix.2 For example, calix[4]arene 1 is chiral
when R3 ) H and R1, R2 * H and can be isolated in optically
active form as long as the ring flip to 2 is prevented by having
large enough substituents R on the phenolic oxygens (at least
n-propyl for R is required) (Figure 1). When the ring flip occurs,
1 becomes racemic, since 2 is its enantiomer. Calix[4]arene 1 can
also be obtained in optically active form if R3 * H, since in this
case the ring flip gives 2, which is a diastereomer. An even more
difficult task is to prepare calixarenes that are chiral as the result
of introduction of substituents on the methylene bridges. In fact,
although a number of mono-, di-, and tetramethylene-substituted
calix[4]arenes have been prepared in the last two decades,3 all were
prepared as racemic compounds, and none have been isolated in
optically active form. The reason for this is clearly linked to the
methods for their preparation, which are based on introduction of
the substituents via reactions that involve intermediates with either
radicals, cations, or carbanions at the methylene carbon or the
intermediacy of compounds that have sp2 carbons bridging the rings.
Calix[4]arene 3 has a plane of symmetry when R1 ) R2 and thus
is not chiral; however, if this is not the case and if R3 * R4, then
3 becomes chiral and should be isolable in optically active form,
since the ring flip to 4 would give a diastereomer.
Figure 1. Intrinsically chiral calix[4]arenes.
Scheme 1
Scheme 2
We have previously developed a new method for the synthesis
of calix[4]arenes that involves triple annulation of the biscarbene
complex 5 with bisalkyne 6 in a process that constructs three of
the five rings of the calix[4]arene in a single step (Scheme 1).4
The yields for this process range only from 22 to 41% but
nonetheless are comparable or superior to those for the macrocy-
clization steps in other methods for the synthesis of unsymmetrical
calix[4]arenes. It was envisioned that it should be possible to utilize
this method for the synthesis of methylene-substituted calix[4]arenes
by incorporating substituents in one or both of the methylenes in
the biscarbene complex 5 and/or one or both of the methylenes in
diyne 6. Indeed, we report here a method that for the first time
allows the direct construction of calix[4]arenes in optically active
form where the chirality results from substitution at the methylene
bridges.
The synthesis of the desired bisalkyne 11 is convergent with
that of the biscarbene complex 13 (Scheme 2). Diol 10 could be
prepared from dialdehyde 85 using Pu’s method for the asymmetric
addition of alkynes to aldehydes.6 This reaction gave diol (S,S)-9
in 56% yield and 99.2% ee along with 42% yield of the
corresponding meso compound. After desilylation and methylation
of diol (R,R)-10, the alkyne functions in (R,R)-11b were hydrozir-
conated, and upon quench with iodine, bis-trans-vinyl iodide 12b
was obtained in 92% yield. The biscarbene complex (R,R)-13b was
then prepared by a modification of the Fischer protocol involving
the addition of a bisvinyllithium to chromium hexacarbonyl
followed by methylation of the intermediate metal acylate.
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18018 J. AM. CHEM. SOC. 2009, 131, 18018–18019
10.1021/ja905990u  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
tetramethoxy-substituted calix[4]arenes. The stereoregulation pos-
sible in this approach has been demonstrated in the controlled
synthesis of two different diastereomers of a tetramethoxy-
substituted calix[4]arene.
Acknowledgment. This work was supported by NSF Grant
CHE-0750319.
Chiral calix[4]arenes with substitution on two of the methylene
Supporting Information Available: Synthetic procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
bridges can be synthesized by reacting the unsubstituted carbene
complex 13a with the disubstituted diyne 11 (Scheme 3). The
dimethoxy diyne 11b reacted to give calix[4]arene 14b in 32%
yield, which exists as 2.6:1 mixture of rapidly interconverting
conformers that can be observed on the NMR time scale.7 Extensive
analysis of 1D NOE and NOESY experiments allowed the
assignment of the major species as the cone conformer 14b, which
has one equatorial and one axial methoxy group.8 The minor
conformer could be only tentatively assigned as the partial cone
14b′ shown in Scheme 3, as a precise assignment of all the protons
and through-space interactions could not be made. The bis-OTBS
diyne (S,S)-11c reacted to give a lower yield (13%) of the bis-
OTBS-substituted calix[4]arene 14c as a 1.3:1 mixture of the same
conformers. Removal of the TBS groups gave calix[4]arene (S,S)-
15, which exists exclusively as the cone conformer. This shift in
conformer equilibrium can be interpreted as a consequence of the
hydrogen-bonding interactions that exist in the cone conformer of
15 but not in the partial cone conformer.
The reaction of biscarbene complex (R,R)-13b with diyne (R,R)-
11b gave calix[4]arene 16 in 30% yield (Scheme 4); despite the
fact that 16 has two axial and two equatorial methoxy groups, it
exists as a single conformer (cone) with a pair of two-hydrogen
singlets at 5.05 and 6.08 ppm.8 One would predict that the reaction
of complex (R,R)-13b with diyne (S,S)-11b would produce an
optically inactive meso calix[4]arene. Indeed, this reaction gave a
26% yield of calix[4]arene 17, which is optically inactive but exists
as a 1:1 mixture of conformers that could not be identified because
of the complexity of the 1H NMR spectrum. Calix[4]arenes 16 and
17 are stereoisomers that differ in that 16 has a trans,cis,trans
relative relationship of the methoxy substituents whereas 17 has a
cis,trans,cis relative relationship.
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In summary, a method for the synthesis of optically active
calix[4]arenes that are chiral as a result of substitution on the
methylene bridges has been described. It has been shown that this
method is suitable for the synthesis of optically active di- and
(7) This reaction was performed on (S,S)-11b.
(8) For a review of the conformations of methylene-substituted calixarenes, see
ref 3p.
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